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NM_001199397.3(NEK1):c.1334A>G (p.His445Arg) AND Short-rib thoracic dysplasia 6 with or without polydactyly

Germline classification:
Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:
Feb 11, 2023
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001330483.13

Allele description [Variation Report for NM_001199397.3(NEK1):c.1334A>G (p.His445Arg)]

NM_001199397.3(NEK1):c.1334A>G (p.His445Arg)

Gene:
NEK1:NIMA related kinase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
4q33
Genomic location:
Preferred name:
NM_001199397.3(NEK1):c.1334A>G (p.His445Arg)
HGVS:
  • NC_000004.12:g.169556028T>C
  • NG_027982.1:g.61600A>G
  • NM_001199397.3:c.1334A>GMANE SELECT
  • NM_001199398.3:c.1334A>G
  • NM_001199399.3:c.1259A>G
  • NM_001199400.3:c.1334A>G
  • NM_001374418.1:c.1334A>G
  • NM_001374419.1:c.1334A>G
  • NM_001374420.1:c.1283A>G
  • NM_001374421.1:c.1208A>G
  • NM_012224.3:c.1334A>G
  • NM_012224.4:c.1334A>G
  • NP_001186326.1:p.His445Arg
  • NP_001186327.1:p.His445Arg
  • NP_001186328.1:p.His420Arg
  • NP_001186329.1:p.His445Arg
  • NP_001361347.1:p.His445Arg
  • NP_001361348.1:p.His445Arg
  • NP_001361349.1:p.His428Arg
  • NP_001361350.1:p.His403Arg
  • NP_036356.1:p.His445Arg
  • NC_000004.11:g.170477179T>C
  • NM_001199397.1:c.1334A>G
  • NM_001199397.3:c.1334A>G
  • NR_164630.1:n.1848A>G
Protein change:
H403R
Links:
dbSNP: rs574204412
NCBI 1000 Genomes Browser:
rs574204412
Molecular consequence:
  • NM_001199397.3:c.1334A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001199398.3:c.1334A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001199399.3:c.1259A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001199400.3:c.1334A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374418.1:c.1334A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374419.1:c.1334A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374420.1:c.1283A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374421.1:c.1208A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_012224.4:c.1334A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_164630.1:n.1848A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Short-rib thoracic dysplasia 6 with or without polydactyly (SRTD6)
Synonyms:
POLYDACTYLY WITH NEONATAL CHONDRODYSTROPHY, TYPE II; Polydactyly with neonatal chondrodystrophy type 2; Majewski Syndrome; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009894; MedGen: C0024507; OMIM: 263520

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001522167Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Apr 17, 2020)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001619222Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely benign
(Feb 11, 2023)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003813596Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Feb 5, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004047991Neuberg Centre For Genomic Medicine, NCGM
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenicgermlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Baylor Genetics, SCV001522167.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001619222.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Revvity Omics, Revvity, SCV003813596.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004047991.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The missense variant c.1334A>G (p.His445Arg) in the NEK1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency of 0.02% in the gnomAD Exomes and 0.06% in 1000 genome database. The amino acid Histidine at position 445 is changed to a Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The residue is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. Another likely pathogenic variant (c.1161_1162insC; p.Glu388ArgfsTer16) in the NEK1 gene was detected in his spouse.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 6, 2024