rs781984274

Positions:

chrX-154352225-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_001110556.2(FLNA):c.6725G>A(p.Arg2242Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,210,093 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).

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 0 hem., cov: 26)

Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 7.82

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:

FLNA (HGNC:):

FLNA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.6725G>A	p.Arg2242Gln	missense_variant	41/48	ENST00000369850.10	NP_001104026.1	P21333-1Q60FE5Q6NXF2
FLNA	NM_001456.4 linkuse as main transcript	c.6701G>A	p.Arg2234Gln	missense_variant	40/47		NP_001447.2	P21333-2Q60FE5Q6NXF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.6725G>A	p.Arg2242Gln	missense_variant	41/48	1	NM_001110556.2	ENSP00000358866.3		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.00000883

AC:

AN:

113281

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35415

show subpopulations

Gnomad AFR

AF:

0.0000320

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000168

AC:

AN:

178731

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

65763

show subpopulations

Gnomad AFR exome

AF:

0.0000823

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000148

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000456

AC:

AN:

1096812

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362700

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.00000883

AC:

AN:

113281

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35415

show subpopulations

Gnomad4 AFR

AF:

0.0000320

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign: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

Mar 21, 2016

- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2021

The p.R2234Q variant (also known as c.6701G>A), located in coding exon 39 of the FLNA gene, results from a G to A substitution at nucleotide position 6701. The arginine at codon 2234 is replaced by glutamine, an amino acid with highly similar properties. Based on data from gnomAD, the A allele has an overall frequency of 0.002% (3/178731) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was 0.01% (2/13480) of East Asian alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

- -

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

Dec 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.;.;.;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D;.;D;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.65

D;D;D;D;D

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

1.6

L;.;.;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.6

D;.;D;D;N

REVEL

Pathogenic

0.72

Sift

Benign

0.046

D;.;D;D;T

Sift4G

Benign

0.074

T;T;T;T;T

Polyphen

0.91

P;.;D;D;.

Vest4

0.78

MutPred

0.59

Loss of methylation at R2242 (P = 0.0149);.;.;.;.;

MVP

0.98

MPC

0.76

ClinPred

0.32

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.55

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