15-48464998-A-G

Position:

• chr15-48464998-A-G

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.4942+570T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 152,070 control chromosomes in the GnomAD database, including 10,318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.34 (10318 hom., cov: 33)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.208

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 15-48464998-A-G is Benign according to our data. Variant chr15-48464998-A-G is described in ClinVar as [Benign]. Clinvar id is 811538.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.4942+570T>C		intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.4942+570T>C		intron_variant			NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.4942+570T>C		intron_variant		1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52160 AN: 151952 Hom.: 10279 Cov.: 33

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.316

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

GnomAD4 genome AF: 0.344 AC: 52265 AN: 152070 Hom.: 10318 Cov.: 33 AF XY: 0.342 AC XY: 25422 AN XY: 74316

Gnomad4 AFR AF: 0.552

Gnomad4 AMR AF: 0.300

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.402

Gnomad4 SAS AF: 0.246

Gnomad4 FIN AF: 0.265

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.315

Alfa AF: 0.270 Hom.: 3098

Bravo AF: 0.357

Asia WGS AF: 0.347 AC: 1208 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 19, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.3
DANN	Benign	0.37

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: rs10519177; hg19: chr15-48757195;