X-154353340-C-T

Position:

chrX-154353340-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_ModerateBP6_Very_StrongBS2

The ENST00000369850.10(FLNA):c.5978G>A(p.Arg1993Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000413 in 1,210,776 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1993W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000062 ( 0 hom., 3 hem., cov: 25)

Exomes 𝑓: 0.000039 ( 0 hom. 16 hem. )

Consequence

FLNA
ENST00000369850.10 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.29

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 -13 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=0.1465728).

BP6

Variant X-154353340-C-T is Benign according to our data. Variant chrX-154353340-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 519890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.5978G>A	p.Arg1993Gln	missense_variant	37/48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4 linkuse as main transcript	c.5954G>A	p.Arg1985Gln	missense_variant	36/47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.5978G>A	p.Arg1993Gln	missense_variant	37/48	1	NM_001110556.2	ENSP00000358866		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000619

AC:

AN:

113011

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

35151

show subpopulations

Gnomad AFR

AF:

0.000193

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:

0.000158

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000606

AC:

AN:

181480

Hom.:

AF XY:

0.0000888

AC XY:

AN XY:

67602

show subpopulations

Gnomad AFR exome

AF:

0.000162

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000105

Gnomad FIN exome

AF:

0.000251

Gnomad NFE exome

AF:

0.0000369

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000392

AC:

AN:

1097765

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

363379

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.000175

Gnomad4 NFE exome

AF:

0.0000332

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000619

AC:

AN:

113011

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

35151

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000158

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000992

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2017

This alteration is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.45

T;.;.;.

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.73

T;T;.;T

M_CAP

Benign

0.058

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Uncertain

-0.095

MutationAssessor

Benign

1.1

L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.7

N;.;N;N

REVEL

Benign

0.26

Sift

Benign

0.22

T;.;T;T

Sift4G

Benign

0.33

T;T;T;T

Polyphen

0.54

P;.;D;D

Vest4

0.18

MutPred

0.45

Loss of solvent accessibility (P = 0.0155);.;.;.;

MVP

0.86

MPC

0.60

ClinPred

0.036

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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