rs61730768

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001110556.2(FLNA):c.1450C>T(p.Arg484Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000975 in 1,210,312 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 40 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R484Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., 14 hem., cov: 24)

Exomes 𝑓: 0.000060 ( 0 hom. 26 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.90

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 -12 ACMG points.

PP2

Missense variant where missense usually causes diseases, FLNA

BP4

Computational evidence support a benign effect (MetaRNN=0.03633821).

BP6

Variant X-154365466-G-A is Benign according to our data. Variant chrX-154365466-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 497691.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00046 (52/113135) while in subpopulation AFR AF= 0.00141 (44/31242). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2 linkuse as main transcript	c.1450C>T	p.Arg484Trp	missense_variant	10/48	ENST00000369850.10
FLNA	NM_001456.4 linkuse as main transcript	c.1450C>T	p.Arg484Trp	missense_variant	10/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10 linkuse as main transcript	c.1450C>T	p.Arg484Trp	missense_variant	10/48	1	NM_001110556.2		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

113082

Hom.:

Cov.:

AF XY:

0.000398

AC XY:

AN XY:

35216

show subpopulations

Gnomad AFR

AF:

0.00141

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000370

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:

0.0000751

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000134

AC:

AN:

179628

Hom.:

AF XY:

0.000120

AC XY:

AN XY:

66792

show subpopulations

Gnomad AFR exome

AF:

0.00164

Gnomad AMR exome

AF:

0.0000732

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000526

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000602

AC:

AN:

1097177

Hom.:

Cov.:

AF XY:

0.0000716

AC XY:

AN XY:

363071

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.0000852

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.0000868

GnomAD4 genome

AF:

0.000460

AC:

AN:

113135

Hom.:

Cov.:

AF XY:

0.000397

AC XY:

AN XY:

35279

show subpopulations

Gnomad4 AFR

AF:

0.00141

Gnomad4 AMR

AF:

0.000370

Gnomad4 ASJ

AF:

0.00

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:

0.0000868

Hom.:

Bravo

AF:

0.000567

ESP6500AA

AF:

0.000604

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000199

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 04, 2016	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2018

This alteration is classified as 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 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.050

Cadd

Benign

Dann

Benign

0.81

DEOGEN2

Pathogenic

0.85

D;.;.;.;.

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

0.98

D;D;.;D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.036

T;T;T;T;T

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.3

M;.;M;M;.

MutationTaster

Benign

0.94

D;D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.2

D;.;D;D;.

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

D;.;D;D;.

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

D;.;D;D;.

Vest4

0.40

MVP

0.92

MPC

1.4

ClinPred

0.36

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.88

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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