14-91870431-T-C

Variant names:

• chr14-91870431-T-C
• rs929608
• NM_006329.4:c.1186-46A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 14 publications found

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]

FBLN5 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal dominant 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• cutis laxa, autosomal recessive, type 1A

  Inheritance: SD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Charcot-Marie-Tooth disease, demyelinating, IIA 1H

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• demyelinating hereditary motor and sensory neuropathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• macular degeneration, age-related, 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• autosomal dominant cutis laxa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary sensorimotor neuropathy with hyperelastic skin

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive cutis laxa type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
FBLN5	NM_006329.4	c.1186-46A>G		intron_variant	Intron 10 of 10	ENST00000342058.9	NP_006320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLN5	ENST00000342058.9	c.1186-46A>G		intron_variant	Intron 10 of 10	1	NM_006329.4	ENSP00000345008.4

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

GnomAD2 exomes AF: 0.493 AC: 122732 AN: 248734 AF XY: 0.499

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 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

African (AFR) AF: 0.246 AC: 8169 AN: 33268

American (AMR) AF: 0.488 AC: 21794 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 13957 AN: 26096

East Asian (EAS) AF: 0.638 AC: 25302 AN: 39658

South Asian (SAS) AF: 0.537 AC: 46168 AN: 86018

European-Finnish (FIN) AF: 0.498 AC: 26585 AN: 53382

Middle Eastern (MID) AF: 0.556 AC: 2340 AN: 4208

European-Non Finnish (NFE) AF: 0.479 AC: 530314 AN: 1106028

Other (OTH) AF: 0.489 AC: 29348 AN: 59976

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

African (AFR) AF: 0.256 AC: 10632 AN: 41514

American (AMR) AF: 0.465 AC: 7112 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1858 AN: 3470

East Asian (EAS) AF: 0.645 AC: 3323 AN: 5154

South Asian (SAS) AF: 0.535 AC: 2584 AN: 4830

European-Finnish (FIN) AF: 0.506 AC: 5362 AN: 10604

Middle Eastern (MID) AF: 0.586 AC: 171 AN: 292

European-Non Finnish (NFE) AF: 0.479 AC: 32537 AN: 67956

Other (OTH) AF: 0.458 AC: 969 AN: 2114

Alfa AF: 0.466 Hom.: 54149

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.46
DANN	Benign	0.70
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs929608; hg19: chr14-92336775;