rs201168500

Positions:

chrX-154350142-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001110556.2(FLNA):c.7222G>A(p.Gly2408Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000237 in 1,210,104 control chromosomes in the GnomAD database, including 1 homozygotes. There are 81 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 0.0012 ( 0 hom., 42 hem., cov: 25)

Exomes 𝑓: 0.00014 ( 1 hom. 39 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 6.09

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 -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNA. . Gene score misZ 3.7802 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked Ehlers-Danlos syndrome, terminal osseous dysplasia-pigmentary defects syndrome, FG syndrome 2, frontometaphyseal dysplasia, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome, otopalatodigital syndrome type 2, periventricular nodular heterotopia, otopalatodigital syndrome type 1, intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked, familial thoracic aortic aneurysm and aortic dissection, congenital short bowel syndrome, frontometaphyseal dysplasia 1, cardiac valvular dysplasia, X-linked.

BP4

Computational evidence support a benign effect (MetaRNN=0.031033784).

BP6

Variant X-154350142-C-T is Benign according to our data. Variant chrX-154350142-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 197499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154350142-C-T is described in Lovd as [Benign]. Variant chrX-154350142-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00122 (138/112664) while in subpopulation AFR AF= 0.00429 (133/31035). AF 95% confidence interval is 0.00369. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 42 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.7222G>A	p.Gly2408Ser	missense_variant	45/48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4 linkuse as main transcript	c.7198G>A	p.Gly2400Ser	missense_variant	44/47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.7222G>A	p.Gly2408Ser	missense_variant	45/48	1	NM_001110556.2	ENSP00000358866		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.00123

AC:

138

AN:

112610

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

34784

show subpopulations

Gnomad AFR

AF:

0.00430

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000372

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000662

GnomAD3 exomes

AF:

0.000352

AC:

AN:

181734

Hom.:

AF XY:

0.000222

AC XY:

AN XY:

67578

show subpopulations

Gnomad AFR exome

AF:

0.00436

Gnomad AMR exome

AF:

0.000329

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.000136

AC:

149

AN:

1097440

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

362884

show subpopulations

Gnomad4 AFR exome

AF:

0.00459

Gnomad4 AMR exome

AF:

0.000341

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000248

Gnomad4 NFE exome

AF:

0.00000356

Gnomad4 OTH exome

AF:

0.000260

GnomAD4 genome

AF:

0.00122

AC:

138

AN:

112664

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

34848

show subpopulations

Gnomad4 AFR

AF:

0.00429

Gnomad4 AMR

AF:

0.000371

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000653

Alfa

AF:

0.000293

Hom.:

Bravo

AF:

0.00148

ESP6500AA

AF:

0.00474

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000347

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 04, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2017

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

FLNA-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2019

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

0.13

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;.;.;.;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;.;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Benign

0.031

T;T;T;T;T

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.1

M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.2

D;.;D;D;.

REVEL

Pathogenic

0.86

Sift

Benign

0.044

D;.;D;D;.

Sift4G

Benign

0.080

T;T;T;T;T

Polyphen

1.0

D;.;D;D;.

Vest4

0.56

MVP

0.97

MPC

0.60

ClinPred

0.093

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.76

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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