rs397515783

Positions:

• chr15-48610774-G-A
• chr15-48610774-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The ENST00000316623.10(FBN1):​c.300C>T​(p.Cys100=) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 ENST00000316623.10 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.56

Genes affected

FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 15-48610774-G-A is Benign according to our data. Variant chr15-48610774-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 42323.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.300C>T	p.Cys100=	synonymous_variant	4/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.300C>T	p.Cys100=	synonymous_variant	3/65		NP_001393645.1
FBN1	NM_001406717.1	c.300C>T	p.Cys100=	synonymous_variant	4/9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.300C>T	p.Cys100=	synonymous_variant	4/66	1	NM_000138.5	ENSP00000325527	P1
FBN1	ENST00000559133.6	c.300C>T	p.Cys100=	synonymous_variant, NMD_transcript_variant	4/67	1		ENSP00000453958
FBN1	ENST00000674301.2	c.300C>T	p.Cys100=	synonymous_variant, NMD_transcript_variant	4/68			ENSP00000501333
FBN1	ENST00000537463.6	c.300C>T	p.Cys100=	synonymous_variant, NMD_transcript_variant	4/31	5		ENSP00000440294

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 19, 2012

Cys100Cys in exon 3 of FBN1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. However, this variant is immediately adjacent to the likely pathogenic variant c.200G>T (p.Cys100Phe) listed above. Testing o f parental DNA would be needed to determine whether these FBN1 variants occur in trans (on separate copies of the gene) or in cis (same copy of the gene; c.299_ 300delinsTT, p.Cys100Phe) or occurred de novo. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397515783; hg19: chr15-48902971;