14-91870431-T-C

Position:

• chr14-91870431-T-C

Variant summary

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

The NM_006329.4(FBLN5):​c.1186-46A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 1,605,466 control chromosomes in the GnomAD database, including 187,602 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14925 hom., cov: 32)
  • Exomes 𝑓: 0.48 (172677 hom.)
• Consequence: FBLN5 NM_006329.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.48

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-91870431-T-C is Benign according to our data. Variant chr14-91870431-T-C is described in ClinVar as [Benign]. Clinvar id is 1227228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBLN5	NM_006329.4	c.1186-46A>G		intron_variant		ENST00000342058.9	NP_006320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBLN5	ENST00000342058.9	c.1186-46A>G		intron_variant		1	NM_006329.4	ENSP00000345008	P1

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64866 AN: 152016 Hom.: 14911 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.644

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.580

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.457

GnomAD3 exomes AF: 0.493 AC: 122732 AN: 248734 Hom.: 31162 AF XY: 0.499 AC XY: 67210 AN XY: 134780

Gnomad AFR exome AF: 0.246

Gnomad AMR exome AF: 0.483

Gnomad ASJ exome AF: 0.529

Gnomad EAS exome AF: 0.653

Gnomad SAS exome AF: 0.539

Gnomad FIN exome AF: 0.499

Gnomad NFE exome AF: 0.489

Gnomad OTH exome AF: 0.501

GnomAD4 exome AF: 0.484 AC: 703977 AN: 1453332 Hom.: 172677 Cov.: 30 AF XY: 0.487 AC XY: 352041 AN XY: 723338

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.488

Gnomad4 ASJ exome AF: 0.535

Gnomad4 EAS exome AF: 0.638

Gnomad4 SAS exome AF: 0.537

Gnomad4 FIN exome AF: 0.498

Gnomad4 NFE exome AF: 0.479

Gnomad4 OTH exome AF: 0.489

GnomAD4 genome AF: 0.427 AC: 64914 AN: 152134 Hom.: 14925 Cov.: 32 AF XY: 0.430 AC XY: 32026 AN XY: 74396

Gnomad4 AFR AF: 0.256

Gnomad4 AMR AF: 0.465

Gnomad4 ASJ AF: 0.535

Gnomad4 EAS AF: 0.645

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.506

Gnomad4 NFE AF: 0.479

Gnomad4 OTH AF: 0.458

Alfa AF: 0.481 Hom.: 37629

Bravo AF: 0.417

Asia WGS AF: 0.532 AC: 1849 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 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.46
DANN	Benign	0.70

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: rs929608; hg19: chr14-92336775;