rs782045915

Positions:

chrX-154362061-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_ModerateBP6_ModerateBS2

The ENST00000369850.10(FLNA):c.2744C>A(p.Thr915Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,208,943 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 56 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.00017 ( 0 hom. 56 hem. )

Consequence

FLNA
ENST00000369850.10 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.119

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 -7 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=0.12278786).

BP6

Variant X-154362061-G-T is Benign according to our data. Variant chrX-154362061-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 239018.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154362061-G-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAdExome4 at 56 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.2744C>A	p.Thr915Asn	missense_variant	19/48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4 linkuse as main transcript	c.2744C>A	p.Thr915Asn	missense_variant	19/47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.2744C>A	p.Thr915Asn	missense_variant	19/48	1	NM_001110556.2	ENSP00000358866		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000628

AC:

AN:

111496

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33692

show subpopulations

Gnomad AFR

AF:

0.0000980

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:

0.0000757

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000220

AC:

AN:

181650

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

67606

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:

0.0000491

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000170

AC:

187

AN:

1097447

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

AN XY:

362857

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000220

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000628

AC:

AN:

111496

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33692

show subpopulations

Gnomad4 AFR

AF:

0.0000980

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:

0.0000757

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.00000825

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.37

T;.;.;.;.

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.73

T;T;.;T;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.12

T;T;T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

-0.20

N;.;N;N;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.57

N;.;N;N;.

REVEL

Benign

0.24

Sift

Benign

0.39

T;.;T;T;.

Sift4G

Benign

0.53

T;T;T;T;T

Polyphen

0.0

B;.;B;B;.

Vest4

0.11

MutPred

0.38

Gain of sheet (P = 0.0221);.;Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;

MVP

0.76

MPC

0.59

ClinPred

0.024

GERP RS

3.0

Varity_R

0.11

gMVP

0.18

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