15-48644769-T-C

Position:

• chr15-48644769-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000138.5(FBN1):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.95

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]

FBN1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48644769-T-C is Pathogenic according to our data. Variant chr15-48644769-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 180349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.1A>G	p.Met1?	start_lost	2/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.1A>G	p.Met1?	start_lost	1/65		NP_001393645.1
FBN1	NM_001406717.1	c.1A>G	p.Met1?	start_lost	2/9		NP_001393646.1
FBN1	NM_001406718.1	c.1A>G	p.Met1?	start_lost	2/3		NP_001393647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.1A>G	p.Met1?	start_lost	2/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Nov 10, 2014	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2018

The p.M1? pathogenic mutation (also known as c.1A>G), located in coding exon 1 of the FBN1 gene, results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. This alteration has been previously identified in a patient reported to have Marfan syndrome (MFS) (Groth KA et al. Genet. Med., 2017 07;19:772-777). Multiple mutations in this codon (c.1A>T, c.2T>A, c.3G>A) have been reported in patients with clinical manifestations of MFS (Rybczynski M et al. Am. J. Med. Genet. A, 2008 Dec;146A:3157-66; Tan L et al. Hum. Mol. Genet., 2017 12;26:4814-4822; Takeda N et al. Circ Genom Precis Med, 2018 Jun;11:e002058). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 28, 2023

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27906200) -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 13, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 180349). Disruption of the initiator codon has been observed in individuals with Marfan syndrome (PMID: 27906200; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the FBN1 mRNA. The next in-frame methionine is located at codon 99. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	0.053
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	-0.23	T
PROVEAN	Benign	-1.1	N;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.027	D;D
Vest4		0.86
MutPred		0.98		Loss of MoRF binding (P = 0.096);Loss of MoRF binding (P = 0.096);
MVP		0.98
ClinPred		0.96	D
GERP RS		4.6

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: rs730880097; hg19: chr15-48936966;