rs730880097

Positions:

• chr15-48644769-T-A
• chr15-48644769-T-C
• chr15-48644769-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The ENST00000316623.10(FBN1):​c.1A>T​(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 ENST00000316623.10 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000316623.10 (FBN1) was described as [Pathogenic] in ClinVar as 495569
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48644769-T-A is Pathogenic according to our data. Variant chr15-48644769-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 577426.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.1A>T	p.Met1?	start_lost	2/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.1A>T	p.Met1?	start_lost	1/65		NP_001393645.1
FBN1	NM_001406717.1	c.1A>T	p.Met1?	start_lost	2/9		NP_001393646.1
FBN1	NM_001406718.1	c.1A>T	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>T	p.Met1?	start_lost	2/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2023

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. Disruption of the initiator codon has been observed in individuals with Marfan syndrome (PMID: 19012347; 19159394. 27906200). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys89Tyr amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19293843, 19720936; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 577426). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.33	.;T
Eigen	Benign	-0.024
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.44	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.50	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.65	T;D
Sift4G	Benign	0.40	T;D
Vest4		0.85
MutPred		0.98		Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);
MVP		0.97
ClinPred		0.93	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;