15-48504949-C-T

Position:

• chr15-48504949-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000138.5(FBN1):​c.1960+76G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,576,856 control chromosomes in the GnomAD database, including 2,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (278 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2688 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0450

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-48504949-C-T is Benign according to our data. Variant chr15-48504949-C-T is described in ClinVar as [Benign]. Clinvar id is 674484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.1960+76G>A		intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.1960+76G>A		intron_variant			NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.1960+76G>A		intron_variant		1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes AF: 0.0499 AC: 7595 AN: 152096 Hom.: 277 Cov.: 33

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.0648

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.0900

Gnomad FIN AF: 0.0742

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0535

Gnomad OTH AF: 0.0607

GnomAD4 exome AF: 0.0578 AC: 82298 AN: 1424642 Hom.: 2688 AF XY: 0.0584 AC XY: 41521 AN XY: 711284

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.0823

Gnomad4 ASJ exome AF: 0.0589

Gnomad4 EAS exome AF: 0.139

Gnomad4 SAS exome AF: 0.0837

Gnomad4 FIN exome AF: 0.0796

Gnomad4 NFE exome AF: 0.0518

Gnomad4 OTH exome AF: 0.0643

GnomAD4 genome AF: 0.0499 AC: 7596 AN: 152214 Hom.: 278 Cov.: 33 AF XY: 0.0512 AC XY: 3812 AN XY: 74424

Gnomad4 AFR AF: 0.0132

Gnomad4 AMR AF: 0.0648

Gnomad4 ASJ AF: 0.0576

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.0885

Gnomad4 FIN AF: 0.0742

Gnomad4 NFE AF: 0.0535

Gnomad4 OTH AF: 0.0662

Alfa AF: 0.0536 Hom.: 241

Bravo AF: 0.0473

Asia WGS AF: 0.164 AC: 570 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.85
CADD	Benign	2.5
DANN	Benign	0.31

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: rs17361868; hg19: chr15-48797146;