rs782539251

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP6

The NM_001110556.2(FLNA):c.1487G>A(p.Arg496Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000033 in 1,210,479 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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. R496W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.86

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, FLNA

BP6

Variant X-154365429-C-T is Benign according to our data. Variant chrX-154365429-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547381.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.1487G>A	p.Arg496Gln	missense_variant	10/48	ENST00000369850.10
FLNA	NM_001456.4 linkuse as main transcript	c.1487G>A	p.Arg496Gln	missense_variant	10/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.1487G>A	p.Arg496Gln	missense_variant	10/48	1	NM_001110556.2		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.00000886

AC:

AN:

112926

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

35060

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000553

AC:

AN:

180966

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67462

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1097553

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363211

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000886

AC:

AN:

112926

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

35060

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FLNA protein function. ClinVar contains an entry for this variant (Variation ID: 547381). This missense change has been observed in individual(s) with clinical features of FLNA-related conditions (PMID: 21520333). This variant is present in population databases (rs782539251, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 496 of the FLNA protein (p.Arg496Gln). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.78

D;.;.;.;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

D;D;.;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.72

D;D;D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.8

M;.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.8

D;.;D;D;.

REVEL

Pathogenic

0.72

Sift

Benign

0.059

T;.;T;T;.

Sift4G

Uncertain

0.011

D;D;D;D;D

Polyphen

0.99

D;.;D;D;.

Vest4

0.59

MutPred

0.47

Loss of MoRF binding (P = 0.0132);.;Loss of MoRF binding (P = 0.0132);Loss of MoRF binding (P = 0.0132);.;

MVP

0.93

MPC

1.5

ClinPred

0.92

GERP RS

4.4

Varity_R

0.89

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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