rs782275601

chrX-154351928-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4

The NM_001110556.2(FLNA):c.6863G>A(p.Arg2288His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,210,113 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 46 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2288C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.00012 ( 0 hom. 46 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 1.62

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 Uncertain_significance. Variant got 0 ACMG points.

PP2

Missense variant where missense usually causes diseases, FLNA

BP4

Computational evidence support a benign effect (MetaRNN=0.31520152).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.6863G>A	p.Arg2288His	missense_variant	42/48	ENST00000369850.10
FLNA	NM_001456.4 linkuse as main transcript	c.6839G>A	p.Arg2280His	missense_variant	41/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.6863G>A	p.Arg2288His	missense_variant	42/48	1	NM_001110556.2		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000266

AC:

AN:

112597

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34743

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000331

AC:

AN:

181154

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67444

show subpopulations

Gnomad AFR exome

AF:

0.0000810

Gnomad AMR exome

AF:

0.00

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:

0.0000494

Gnomad OTH exome

AF:

0.000225

GnomAD4 exome

AF:

0.000118

AC:

129

AN:

1097516

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

363096

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000145

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000266

AC:

AN:

112597

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34743

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000564

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 06, 2021

DNA sequence analysis of the FLNA gene demonstrated a sequence change, c.6839G>A, in exon 41 that results in an amino acid change, p.Arg2280His. This sequence change does not appear to have been previously described in individuals with FLNA-related disorders. This sequence change has been described in the gnomAD database with a low frequency of 0.008% in African/African American subpopulation (dbSNP rs782275601). The p.Arg2280His change affects a highly conserved amino acid residue located in a domain of the FLNA protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg2280His substitution. Due to the lack of sufficient evidence, the clinical significance of the p.Arg2280His change remains unknown at this time. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2019

The p.R2280H variant (also known as c.6839G>A), located in coding exon 40 of the FLNA gene, results from a G to A substitution at nucleotide position 6839. The arginine at codon 2280 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Heterotopia, periventricular, X-linked dominant

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Nov 02, 2023

- -

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

Sep 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Uncertain

-0.010

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Uncertain

0.70

D;.;.;.;.;.

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.93

D;D;.;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.32

T;T;T;T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

0.93

L;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.4

N;.;N;N;.;N

REVEL

Uncertain

0.60

Sift

Benign

0.27

T;.;T;T;.;T

Sift4G

Benign

0.33

T;T;T;T;T;T

Polyphen

0.72

P;.;B;B;.;.

Vest4

0.092

MutPred

0.42

Gain of ubiquitination at K2289 (P = 0.0668);.;.;.;.;.;

MVP

0.97

MPC

0.65

ClinPred

0.11

GERP RS

4.3

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.70

gMVP

0.52

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