14-91936950-C-T

Position:

chr14-91936950-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000342058.9(FBLN5):c.376G>A(p.Val126Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,614,216 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 8 hom. )

Consequence

FBLN5
ENST00000342058.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:7

Conservation

PhyloP100: 3.08

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019288361).

BP6

Variant 14-91936950-C-T is Benign according to our data. Variant chr14-91936950-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218360.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=6}. Variant chr14-91936950-C-T is described in Lovd as [Likely_benign]. Variant chr14-91936950-C-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00194 (296/152332) while in subpopulation NFE AF= 0.00344 (234/68038). AF 95% confidence interval is 0.00308. There are 0 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBLN5	NM_006329.4 linkuse as main transcript	c.376G>A	p.Val126Met	missense_variant	4/11	ENST00000342058.9	NP_006320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBLN5	ENST00000342058.9 linkuse as main transcript	c.376G>A	p.Val126Met	missense_variant	4/11	1	NM_006329.4	ENSP00000345008	P1

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

297

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00345

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00183

AC:

456

AN:

249058

Hom.:

AF XY:

0.00165

AC XY:

222

AN XY:

134820

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00323

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00300

AC:

4381

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

2128

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00172

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000524

Gnomad4 NFE exome

AF:

0.00366

Gnomad4 OTH exome

AF:

0.00306

GnomAD4 genome

AF:

0.00194

AC:

296

AN:

152332

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

127

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00344

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00315

Hom.:

Bravo

AF:

0.00196

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00186

AC:

226

EpiCase

AF:

0.00305

EpiControl

AF:

0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 07, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	FBLN5: BS3:Supporting -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2020	Identified in patients with age-related macular degeneration or spinal Charcot-Marie-Tooth, as well as in control cohorts (Lotery et al., 2006; Auer-Grumbach et al., 2011; Duvvari et al., 2016); Expression of this variant in COS-7 cells demonstrated no significant effect on fibulin-5 protein secretion or quantity compared to wild-type (Lotery et al., 2006), and biophysical techniques did not suggest any gross structural changes in association with this variant (Jones et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar as either a variant of uncertain significance or a likely benign variant but additional evidence is not available (ClinVar Variant ID# 218360; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 21616967, 20389311, 27007659, 21576112, 22943132, 23293578, 16652333, 20007835, 23532871) -

Charcot-Marie-Tooth disease, demyelinating, IIA 1H

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2011

- -

FBLN5-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 06, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Macular degeneration, age-related, 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cutis laxa

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.098

T;T;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.071

MetaRNN

Benign

0.019

T;T;T

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

1.4

.;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.88

N;N;N

REVEL

Uncertain

0.52

Sift

Uncertain

0.0080

D;T;T

Sift4G

Benign

0.086

T;T;T

Polyphen

0.99

D;P;P

Vest4

0.60

MVP

0.71

MPC

0.69

ClinPred

0.020

GERP RS

4.8

Varity_R

0.25

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over