rs886039072

Positions:

• chr15-48644767-C-A
• chr15-48644767-C-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000138.5(FBN1):​c.3G>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. 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:2
• Conservation: PhyloP100: 2.47

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 Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000138.5 (FBN1) was described as [Pathogenic] in ClinVar as 495569
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48644767-C-A is Pathogenic according to our data. Variant chr15-48644767-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 264175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.3G>T	p.Met1?	start_lost	2/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

May 01, 2019

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2021

The p.M1? pathogenic mutation (also known as c.3G>T) is located in coding exon 1 of the FBN1 gene and results from a G to T substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This alteration has been reported in individuals suspected to have Marfan syndrome (Rybczynski M et al., Am. J. Med. Genet. A 2008 Dec; 146A(24):3157-66; Söylen B et al., Clin. Genet. 2009 Mar; 75(3):265-70; Yang H et al., Sci Rep. 2016 Sep 9;6:33002; Tan L et al., Hum Mol Genet. 2017 Dec 15;26(24):4814-4822). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	-0.0034	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-1.1	N;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.028	D;D
Sift4G	Uncertain	0.046	D;D
Vest4		0.74
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.027);Gain of catalytic residue at M1 (P = 0.027);
MVP		0.97
ClinPred		0.99	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: rs886039072; hg19: chr15-48936964;