rs36051194

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001110556.2(FLNA):c.1286C>T(p.Thr429Met) variant causes a missense change. The variant allele was found at a frequency of 0.0169 in 1,209,111 control chromosomes in the GnomAD database, including 168 homozygotes. There are 6,589 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 12 hom., 608 hem., cov: 24)

Exomes 𝑓: 0.017 ( 156 hom. 5981 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 4.01

Variant links:

Genes affected

FLNA (HGNC:3754): (filamin A) The protein encoded by this gene is an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins. The encoded protein is involved in remodeling the cytoskeleton to effect changes in cell shape and migration. This protein interacts with integrins, transmembrane receptor complexes, and second messengers. Defects in this gene are a cause of several syndromes, including periventricular nodular heterotopias (PVNH1, PVNH4), otopalatodigital syndromes (OPD1, OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

FLNA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008827686).

BP6

Variant X-154366167-G-A is Benign according to our data. Variant chrX-154366167-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154366167-G-A is described in Lovd as [Benign]. Variant chrX-154366167-G-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0143 (1607/112464) while in subpopulation NFE AF= 0.018 (953/53083). AF 95% confidence interval is 0.017. There are 12 homozygotes in gnomad4. There are 608 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2 link	c.1286C>T	p.Thr429Met	missense_variant	Exon 9 of 48	ENST00000369850.10	NP_001104026.1	P21333-1Q60FE5Q6NXF2
FLNA	NM_001456.4 link	c.1286C>T	p.Thr429Met	missense_variant	Exon 9 of 47		NP_001447.2	P21333-2Q60FE5Q6NXF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10 link	c.1286C>T	p.Thr429Met	missense_variant	Exon 9 of 48	1	NM_001110556.2	ENSP00000358866.3		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

1608

AN:

112411

Hom.:

Cov.:

AF XY:

0.0176

AC XY:

609

AN XY:

34625

show subpopulations

Gnomad AFR

AF:

0.00252

Gnomad AMI

AF:

0.0248

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.0113

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0645

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0180

Gnomad OTH

AF:

0.0119

GnomAD3 exomes

AF:

0.0151

AC:

2724

AN:

180120

Hom.:

AF XY:

0.0145

AC XY:

969

AN XY:

66682

show subpopulations

Gnomad AFR exome

AF:

0.00267

Gnomad AMR exome

AF:

0.00424

Gnomad ASJ exome

AF:

0.0108

Gnomad EAS exome

AF:

0.0000739

Gnomad SAS exome

AF:

0.000367

Gnomad FIN exome

AF:

0.0598

Gnomad NFE exome

AF:

0.0186

Gnomad OTH exome

AF:

0.0175

GnomAD4 exome

AF:

0.0172

AC:

18849

AN:

1096647

Hom.:

156

Cov.:

AF XY:

0.0165

AC XY:

5981

AN XY:

362695

show subpopulations

Gnomad4 AFR exome

AF:

0.00220

Gnomad4 AMR exome

AF:

0.00454

Gnomad4 ASJ exome

AF:

0.0109

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.000480

Gnomad4 FIN exome

AF:

0.0585

Gnomad4 NFE exome

AF:

0.0183

Gnomad4 OTH exome

AF:

0.0142

GnomAD4 genome

AF:

0.0143

AC:

1607

AN:

112464

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

608

AN XY:

34688

show subpopulations

Gnomad4 AFR

AF:

0.00251

Gnomad4 AMR

AF:

0.0104

Gnomad4 ASJ

AF:

0.0113

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0645

Gnomad4 NFE

AF:

0.0180

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.0162

Hom.:

674

Bravo

AF:

0.0108

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0204

AC:

ESP6500AA

AF:

0.00246

AC:

ESP6500EA

AF:

0.0163

AC:

107

ExAC

AF:

0.0153

AC:

1856

EpiCase

AF:

0.0172

EpiControl

AF:

0.0145

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 08, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 10, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 20, 2012

Claritas Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Oct 24, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Apr 16, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Melnick-Needles syndrome;C0262436:Cardiac valvular dysplasia, X-linked;C0265251:Oto-palato-digital syndrome, type I;C1844696:Oto-palato-digital syndrome, type II;C1845902:FG syndrome 2;C1846129:Terminal osseous dysplasia-pigmentary defects syndrome;C1848213:Heterotopia, periventricular, X-linked dominant;C2746068:Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked;C4281559:Frontometaphyseal dysplasia 1

Benign:1

Nov 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FLNA-related disorder

Benign:1

Mar 04, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.58

DEOGEN2

Uncertain

0.79

D;.;.;.;.

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.91

D;D;.;D;D

MetaRNN

Benign

0.0088

T;T;T;T;T

MetaSVM

Uncertain

0.081

MutationAssessor

Uncertain

2.5

M;.;M;M;.

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.8

D;.;D;D;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.022

D;.;D;D;.

Sift4G

Uncertain

0.041

D;D;D;D;T

Polyphen

1.0

D;.;P;P;.

Vest4

0.44

MPC

1.2

ClinPred

0.030

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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