NM_000138.4(FBN1):c.5423-4G>A AND not specified

Clinical significance:Likely benign (Last evaluated: Mar 8, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000277311.4

Allele description [Variation Report for NM_000138.4(FBN1):c.5423-4G>A]

NM_000138.4(FBN1):c.5423-4G>A

Gene:
FBN1:fibrillin 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q21.1
Genomic location:
Preferred name:
NM_000138.4(FBN1):c.5423-4G>A
HGVS:
  • NC_000015.10:g.48452688C>T
  • NG_008805.2:g.198101G>A
  • NM_000138.4:c.5423-4G>A
  • LRG_778t1:c.5423-4G>A
  • LRG_778:g.198101G>A
  • NC_000015.9:g.48744885C>T
  • NM_000138.4(FBN1):c.5423-4G>A
Links:
dbSNP: rs377036485
NCBI 1000 Genomes Browser:
rs377036485
Molecular consequence:
  • NM_000138.4:c.5423-4G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000522931GeneDxcriteria provided, single submitter
Likely benign
(Mar 8, 2017)
germlineclinical testing

Citation Link,

SCV001422579Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedLikely benign
(Jan 22, 2020)
germlinecuration

Citation Link

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000522931.4

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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

From Broad Institute Rare Disease Group, Broad Institute, SCV001422579.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.5423-4G>A variant in FBN1 has not been previously reported in individuals with Marfan Syndrome but has been reported as likely benign and a VUS in ClinVar (Variation ID: 237098). This variant has been identified in 0.1162% (29/24966) of African chromosomes, 0.008469% (3/35424) of Latino chromosomes, and 0.0007757% (1/128922) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs377036485). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The number of missense variants reported in FBN1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4, BP7, PP2 (Richards 2015).

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

Last Updated: May 23, 2021

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