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NM_001291303.3(FAT4):c.6719C>T (p.Thr2240Ile) AND not provided

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Oct 26, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000489669.2

Allele description [Variation Report for NM_001291303.3(FAT4):c.6719C>T (p.Thr2240Ile)]

NM_001291303.3(FAT4):c.6719C>T (p.Thr2240Ile)

Gene:
FAT4:FAT atypical cadherin 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
4q28.1
Genomic location:
Preferred name:
NM_001291303.3(FAT4):c.6719C>T (p.Thr2240Ile)
HGVS:
  • NC_000004.12:g.125415682C>T
  • NG_033865.1:g.104271C>T
  • NM_001291285.3:c.6719C>T
  • NM_001291303.3:c.6719C>TMANE SELECT
  • NM_024582.6:c.6719C>T
  • NP_001278214.1:p.Thr2240Ile
  • NP_001278232.1:p.Thr2240Ile
  • NP_078858.4:p.Thr2240Ile
  • NP_078858.4:p.Thr2240Ile
  • NC_000004.11:g.126336837C>T
  • NM_024582.4:c.6719C>T
Protein change:
T2240I
Links:
dbSNP: rs774192877
NCBI 1000 Genomes Browser:
rs774192877
Molecular consequence:
  • NM_001291285.3:c.6719C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001291303.3:c.6719C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_024582.6:c.6719C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: CN517202

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000577456GeneDx
criteria provided, single submitter

(GeneDx Variant Classification (06012015))		Uncertain significance
(Mar 29, 2017) 		germlineclinical testing

Citation Link,

SCV002984951Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Oct 26, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot 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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From GeneDx, SCV000577456.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

A variant of uncertain significance has been identified in the FAT4 gene. The T2240I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T2240I variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T2240I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

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

From Invitae, SCV002984951.1

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

Description

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2240 of the FAT4 protein (p.Thr2240Ile). This variant is present in population databases (rs774192877, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with FAT4-related conditions. ClinVar contains an entry for this variant (Variation ID: 426887). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FAT4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Feb 7, 2023