rs1557178202

Positions:

chrX-154362314-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4BP6_Moderate

The NM_001110556.2(FLNA):c.2584A>G(p.Ile862Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,209,113 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I862T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 0.589

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, FLNA

BP4

Computational evidence support a benign effect (MetaRNN=0.31441897).

BP6

Variant X-154362314-T-C is Benign according to our data. Variant chrX-154362314-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 533582.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.2584A>G	p.Ile862Val	missense_variant	18/48	ENST00000369850.10
FLNA	NM_001456.4 linkuse as main transcript	c.2584A>G	p.Ile862Val	missense_variant	18/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.2584A>G	p.Ile862Val	missense_variant	18/48	1	NM_001110556.2		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111708

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33912

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000942

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:

0.00000553

AC:

AN:

180951

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67303

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097405

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363073

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111708

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33912

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000942

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

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Heterotopia, periventricular, X-linked dominant

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Genomics Laboratory, Stanford Medicine

Jun 22, 2021

The p.Ile862Val variant in the FLNA gene has not been previously reported in association with disease. The p.Ile862Val variant has been identified in 1/27,369 Latino chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). While this variant was present in one individual in gnomAD, this individual is female, and this variant was not observed in any males. Given the possibility of milder phenotypes as discussed above, criteria for low frequency in the general population was applied. The FLNA gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Ile862Val variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; PP2] -

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

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

T;.;.;.;.

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.90

D;D;.;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.31

T;T;T;T;T

MetaSVM

Uncertain

-0.012

MutationAssessor

Benign

1.8

L;.;L;L;.

MutationTaster

Benign

0.75

D;D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.68

N;.;N;N;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.0050

D;.;D;D;.

Sift4G

Benign

0.20

T;T;T;T;T

Polyphen

0.0070

B;.;B;B;.

Vest4

0.17

MutPred

0.66

Gain of ubiquitination at K865 (P = 0.0605);.;Gain of ubiquitination at K865 (P = 0.0605);Gain of ubiquitination at K865 (P = 0.0605);.;

MVP

0.91

MPC

0.44

ClinPred

0.42

GERP RS

4.9

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.23

gMVP

0.36

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