rs11070643

chr15-48474981-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000138.5(FBN1):c.3965-331G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 152,164 control chromosomes in the GnomAD database, including 417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.039 (417 hom., cov: 32)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.32

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 15-48474981-C-T is Benign according to our data. Variant chr15-48474981-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 681280.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.3965-331G>A		intron_variant		ENST00000316623.10
FBN1	NM_001406716.1	c.3965-331G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.3965-331G>A		intron_variant		1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5914 AN: 152046 Hom.: 414 Cov.: 32

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0834

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.0685

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0489

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0390 AC: 5934 AN: 152164 Hom.: 417 Cov.: 32 AF XY: 0.0429 AC XY: 3190 AN XY: 74388

Gnomad4 AFR AF: 0.0243

Gnomad4 AMR AF: 0.0840

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.322

Gnomad4 SAS AF: 0.0689

Gnomad4 FIN AF: 0.0205

Gnomad4 NFE AF: 0.0173

Gnomad4 OTH AF: 0.0493

Alfa AF: 0.0236 Hom.: 7

Bravo AF: 0.0452

Asia WGS AF: 0.185 AC: 638 AN: 3452

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.28
Dann	Benign	0.32

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: rs11070643; hg19: chr15-48767178;