rs200053635

Positions:

chrX-154362534-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001110556.2(FLNA):c.2449C>T(p.Pro817Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000446 in 1,210,103 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 200 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P817P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., 11 hem., cov: 24)

Exomes 𝑓: 0.00046 ( 0 hom. 189 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11O:1

Conservation

PhyloP100: 3.46

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 -10 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=0.0738256).

BP6

Variant X-154362534-G-A is Benign according to our data. Variant chrX-154362534-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194727.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=4, Uncertain_significance=1, Benign=4}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000311 (35/112721) while in subpopulation SAS AF= 0.0018 (5/2780). AF 95% confidence interval is 0.000708. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.2449C>T	p.Pro817Ser	missense_variant	17/48	ENST00000369850.10
FLNA	NM_001456.4 linkuse as main transcript	c.2449C>T	p.Pro817Ser	missense_variant	17/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.2449C>T	p.Pro817Ser	missense_variant	17/48	1	NM_001110556.2		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.000311

AC:

AN:

112721

Hom.:

Cov.:

AF XY:

0.000315

AC XY:

AN XY:

34873

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000933

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00180

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000545

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000454

AC:

AN:

180748

Hom.:

AF XY:

0.000610

AC XY:

AN XY:

67230

show subpopulations

Gnomad AFR exome

AF:

0.0000809

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000787

Gnomad FIN exome

AF:

0.000251

Gnomad NFE exome

AF:

0.000745

Gnomad OTH exome

AF:

0.000225

GnomAD4 exome

AF:

0.000460

AC:

505

AN:

1097382

Hom.:

Cov.:

AF XY:

0.000520

AC XY:

189

AN XY:

363178

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.000155

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000886

Gnomad4 FIN exome

AF:

0.000100

Gnomad4 NFE exome

AF:

0.000504

Gnomad4 OTH exome

AF:

0.000434

GnomAD4 genome

AF:

0.000311

AC:

AN:

112721

Hom.:

Cov.:

AF XY:

0.000315

AC XY:

AN XY:

34873

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000933

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00180

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000545

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000600

Hom.:

Bravo

AF:

0.000200

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000305

AC:

ExAC

AF:

0.000545

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:11Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 20, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2016	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2023	Variant summary: FLNA c.2449C>T (p.Pro817Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 180748 control chromosomes, predominantly at a frequency of 0.00079 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2528 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNA causing Periventricular Nodular Heterotopia phenotype (3.1e-07), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.2449C>T has been reported in the literature in individuals affected with various diseases such as disorders of gonadal development, congenital macrothrombocytopenia and connective tissue disorders, without strong evidence for causality (examples, Renner_2019, Zidoune_2022, Smolag_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Periventricular Nodular Heterotopia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30675029, 34858435, 36110220). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Benign/Likely benign, n=7; VUS, n=2). Based on the evidence outlined above, the variant was classified as benign. -

FLNA-related disorder

Benign:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 24, 2019	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). -

Disorder of sexual differentiation

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Human Developmental Genetics, Institut Pasteur

Aug 15, 2021

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 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 11, 2024

- -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

D;.;.;.;.

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.96

D;D;.;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.074

T;T;T;T;T

MetaSVM

Uncertain

-0.016

MutationAssessor

Uncertain

2.4

M;.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.3

D;.;D;D;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.0090

D;.;D;D;.

Sift4G

Uncertain

0.024

D;D;D;D;D

Polyphen

1.0

D;.;B;B;.

Vest4

0.11

MVP

0.86

MPC

0.68

ClinPred

0.088

GERP RS

4.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Varity_R

0.21

gMVP

0.51

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