X-154362500-C-T

Position:

chrX-154362500-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_001110556.2(FLNA):c.2483G>A(p.Arg828His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,210,143 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.000020 ( 0 hom. 10 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.71

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 Likely_benign. Variant got -4 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=0.32434303).

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.2483G>A	p.Arg828His	missense_variant	17/48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4 linkuse as main transcript	c.2483G>A	p.Arg828His	missense_variant	17/47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.2483G>A	p.Arg828His	missense_variant	17/48	1	NM_001110556.2	ENSP00000358866		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

112946

Hom.:

Cov.:

AF XY:

0.0000570

AC XY:

AN XY:

35086

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000929

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

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1097197

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

362905

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:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000190

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000177

AC:

AN:

112946

Hom.:

Cov.:

AF XY:

0.0000570

AC XY:

AN XY:

35086

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000929

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

Bravo

AF:

0.00000378

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 17, 2024

- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 828 of the FLNA protein (p.Arg828His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 567520). 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 with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

0.0055

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.50

T;.;.;.;.

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.65

T;T;.;T;T

M_CAP

Benign

0.066

MetaRNN

Benign

0.32

T;T;T;T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

0.12

N;.;N;N;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.4

N;.;N;N;.

REVEL

Uncertain

0.43

Sift

Benign

0.45

T;.;T;T;.

Sift4G

Benign

0.35

T;T;T;T;T

Polyphen

0.99

D;.;B;B;.

Vest4

0.28

MutPred

0.54

Loss of catalytic residue at R828 (P = 0.0676);.;Loss of catalytic residue at R828 (P = 0.0676);Loss of catalytic residue at R828 (P = 0.0676);.;

MVP

0.94

MPC

0.65

ClinPred

0.60

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.25

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