rs2246416

Positions:

• chr14-91924276-A-G

Variant summary

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

The ENST00000342058.9(FBLN5):​c.379+12671T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 152,196 control chromosomes in the GnomAD database, including 7,110 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 0.30 (7110 hom., cov: 33)
• Consequence: FBLN5 ENST00000342058.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.359

Genes affected

FBLN5 (HGNC:3602): (fibulin 5) The protein encoded by this gene is a secreted, extracellular matrix protein containing an Arg-Gly-Asp (RGD) motif and calcium-binding EGF-like domains. It promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. It is prominently expressed in developing arteries but less so in adult vessels. However, its expression is reinduced in balloon-injured vessels and atherosclerotic lesions, notably in intimal vascular smooth muscle cells and endothelial cells. Therefore, the protein encoded by this gene may play a role in vascular development and remodeling. Defects in this gene are a cause of autosomal dominant cutis laxa, autosomal recessive cutis laxa type I (CL type I), and age-related macular degeneration type 3 (ARMD3). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBLN5	NM_006329.4	c.379+12671T>C		intron_variant		ENST00000342058.9	NP_006320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBLN5	ENST00000342058.9	c.379+12671T>C		intron_variant		1	NM_006329.4	ENSP00000345008	P1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46101 AN: 152078 Hom.: 7109 Cov.: 33

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.322

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

GnomAD4 genome AF: 0.303 AC: 46113 AN: 152196 Hom.: 7110 Cov.: 33 AF XY: 0.305 AC XY: 22661 AN XY: 74404

Gnomad4 AFR AF: 0.280

Gnomad4 AMR AF: 0.288

Gnomad4 ASJ AF: 0.372

Gnomad4 EAS AF: 0.482

Gnomad4 SAS AF: 0.392

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.297

Gnomad4 OTH AF: 0.316

Alfa AF: 0.304 Hom.: 4193

Bravo AF: 0.304

Asia WGS AF: 0.412 AC: 1434 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.75

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: rs2246416; hg19: chr14-92390620;