15-48618043-A-G

Position:

• chr15-48618043-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000138.5(FBN1):​c.165-4951T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 151,900 control chromosomes in the GnomAD database, including 11,948 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (11948 hom., cov: 31)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.279

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.165-4951T>C		intron_variant		ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.165-4951T>C		intron_variant			NP_001393645.1
FBN1	NM_001406717.1	c.165-4951T>C		intron_variant			NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.165-4951T>C		intron_variant		1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.165-4951T>C		intron_variant		1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.165-4951T>C		intron_variant		5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.165-4951T>C		intron_variant				ENSP00000501333.2

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55153 AN: 151786 Hom.: 11915 Cov.: 31

Gnomad AFR AF: 0.614

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.329

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

GnomAD4 genome AF: 0.364 AC: 55247 AN: 151900 Hom.: 11948 Cov.: 31 AF XY: 0.361 AC XY: 26835 AN XY: 74248

Gnomad4 AFR AF: 0.614

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.396

Gnomad4 SAS AF: 0.281

Gnomad4 FIN AF: 0.273

Gnomad4 NFE AF: 0.252

Gnomad4 OTH AF: 0.329

Alfa AF: 0.265 Hom.: 9171

Bravo AF: 0.376

Asia WGS AF: 0.378 AC: 1315 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.1
DANN	Benign	0.71

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: rs1807301; hg19: chr15-48910240;