rs35986650

Positions:

chrX-154362550-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001110556.2(FLNA):c.2433C>T(p.Ala811=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,210,108 control chromosomes in the GnomAD database, including 49 homozygotes. There are 743 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 0.012 ( 19 hom., 350 hem., cov: 24)

Exomes 𝑓: 0.0013 ( 30 hom. 393 hem. )

Consequence

FLNA
NM_001110556.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.427

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant X-154362550-G-A is Benign according to our data. Variant chrX-154362550-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154362550-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.427 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1302/112707) while in subpopulation AFR AF= 0.0392 (1216/31045). AF 95% confidence interval is 0.0373. There are 19 homozygotes in gnomad4. There are 350 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.2433C>T	p.Ala811=	synonymous_variant	17/48	ENST00000369850.10
FLNA	NM_001456.4 linkuse as main transcript	c.2433C>T	p.Ala811=	synonymous_variant	17/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.2433C>T	p.Ala811=	synonymous_variant	17/48	1	NM_001110556.2		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1298

AN:

112653

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

349

AN XY:

34797

show subpopulations

Gnomad AFR

AF:

0.0391

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00597

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.000131

Gnomad OTH

AF:

0.00919

GnomAD3 exomes

AF:

0.00338

AC:

611

AN:

180603

Hom.:

AF XY:

0.00202

AC XY:

136

AN XY:

67165

show subpopulations

Gnomad AFR exome

AF:

0.0425

Gnomad AMR exome

AF:

0.00237

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000157

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000870

Gnomad OTH exome

AF:

0.00225

GnomAD4 exome

AF:

0.00132

AC:

1451

AN:

1097401

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

393

AN XY:

363187

show subpopulations

Gnomad4 AFR exome

AF:

0.0425

Gnomad4 AMR exome

AF:

0.00295

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000739

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000831

Gnomad4 OTH exome

AF:

0.00299

GnomAD4 genome

AF:

0.0116

AC:

1302

AN:

112707

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

350

AN XY:

34861

show subpopulations

Gnomad4 AFR

AF:

0.0392

Gnomad4 AMR

AF:

0.00596

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000131

Gnomad4 OTH

AF:

0.00907

Alfa

AF:

0.00581

Hom.:

Bravo

AF:

0.0143

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 10, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2014	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2015

This alteration is classified as likely 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.2

DANN

Benign

0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

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