rs782371735

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP6_Very_StrongBS1BS2

The NM_001110556.2(FLNA):c.1451G>A(p.Arg484Gln) 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 1,210,301 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. 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. R484W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000041 ( 0 hom. 15 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:3

Conservation

PhyloP100: 3.35

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 -15 ACMG points.

PP2

Missense variant where missense usually causes diseases, FLNA

BP6

Variant X-154365465-C-T is Benign according to our data. Variant chrX-154365465-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 213520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000041 (45/1097234) while in subpopulation MID AF= 0.00145 (6/4133). AF 95% confidence interval is 0.000631. There are 0 homozygotes in gnomad4_exome. There are 15 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.1451G>A	p.Arg484Gln	missense_variant	10/48	ENST00000369850.10
FLNA	NM_001456.4 linkuse as main transcript	c.1451G>A	p.Arg484Gln	missense_variant	10/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.1451G>A	p.Arg484Gln	missense_variant	10/48	1	NM_001110556.2		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000442

AC:

AN:

113067

Hom.:

Cov.:

AF XY:

0.0000284

AC XY:

AN XY:

35223

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000376

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000751

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000779

AC:

AN:

179740

Hom.:

AF XY:

0.0000898

AC XY:

AN XY:

66844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000732

Gnomad ASJ exome

AF:

0.000136

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000525

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000100

Gnomad OTH exome

AF:

0.000453

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1097234

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

363116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.000155

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000321

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.0000442

AC:

AN:

113067

Hom.:

Cov.:

AF XY:

0.0000284

AC XY:

AN XY:

35223

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000376

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000751

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000580

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Heterotopia, periventricular, X-linked dominant

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Sezerman Lab, Dept of Biostatistics and Bioinformatics, Acibadem Mehmet Ali Aydinlar University

Oct 11, 2020

The p.Arg484Gln variant in FLNA has been reported in two Turkish brothers (age of onset: 16 and 11; with healthy parents and grandparents) with occipital lobe epilepsy and epileptic status in sleep. They are diagnosed as periventricular nodular heterotopia (PVNH), which is a cell migration disorder. Heterozygous mother is asymptomatic, and healthy father carries the reference allele. Generally, heterozygous females carrying PVNH-related missense mutations have mild or no symptoms as in the mother. This is the reason of the presence of this variant (rs782371735) in the population databases (e.g. ExAC 0.009%). On the other hand, only a few males (<40) can survive, and they should have compensating mechanisms for the function of FLNA. Therefore, we investigated the etiology of the disease by observing the impact of PVNH-related FLNA mutations found in the liveborn males on the structure and dynamics of FLNA protein via molecular dynamics (MD) simulations. For the p.Arg484Gln variant, MD studies showed that the mutation does not lead to a general misfolding or permanent loss of function. Instead, it may cause a temporary dysfunction since we observed significant changes in the fluctuations (higher), solvent-accessible surface area (lower), conformational space and local interactions (i.e. H-bonds and salt bridges within 10 Ã… of the mutation site) in the half of the MD simulations. This event might lead to formation of nodules in the periventricular region and might also compensate the cell migration function. Thus, the males who have this variant can survive with the only copy of mutated FLNA. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 20, 2022

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 12, 2020

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31625567) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.15

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Uncertain

0.76

D;.;.;.;.

FATHMM_MKL

Benign

0.75

LIST_S2

Pathogenic

0.99

D;D;.;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Uncertain

0.63

D;D;D;D;D

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.7

M;.;M;M;.

MutationTaster

Benign

0.79

D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.8

D;.;D;D;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.0020

D;.;D;D;.

Sift4G

Uncertain

0.015

D;D;D;D;D

Polyphen

1.0

D;.;D;D;.

Vest4

0.44

MVP

0.92

MPC

1.5

ClinPred

0.34

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.79

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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