rs782469665

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6

The NM_001110556.2(FLNA):c.5059A>G(p.Thr1687Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000578 in 1,211,243 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 26)

Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 4.97

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3018989).

BP6

Variant X-154354983-T-C is Benign according to our data. Variant chrX-154354983-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 569597.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2 link	c.5059A>G	p.Thr1687Ala	missense_variant	Exon 31 of 48	ENST00000369850.10	NP_001104026.1	P21333-1Q60FE5Q6NXF2
FLNA	NM_001456.4 link	c.5035A>G	p.Thr1679Ala	missense_variant	Exon 30 of 47		NP_001447.2	P21333-2Q60FE5Q6NXF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10 link	c.5059A>G	p.Thr1687Ala	missense_variant	Exon 31 of 48	1	NM_001110556.2	ENSP00000358866.3		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000176

AC:

AN:

113424

Hom.:

Cov.:

AF XY:

0.0000281

AC XY:

AN XY:

35560

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000184

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:

0.0000220

AC:

AN:

181461

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

67561

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

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:

0.00000455

AC:

AN:

1097819

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363365

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000142

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:

0.0000176

AC:

AN:

113424

Hom.:

Cov.:

AF XY:

0.0000281

AC XY:

AN XY:

35560

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000184

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

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 28, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Feb 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FLNA c.5035A>G; p.Thr1679Ala variant (rs782469665), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 569597). This variant is found in the general population with an overall allele frequency of 0.002% (4/181461 alleles, including 2 hemizygotes) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.272). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Sep 19, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.60

D;.;.;.;.

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

D;D;.;D;D

M_CAP

Benign

0.070

MetaRNN

Benign

0.30

T;T;T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

0.085

N;.;.;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.3

N;.;N;N;.

REVEL

Benign

0.27

Sift

Benign

0.15

T;.;T;T;.

Sift4G

Benign

0.36

T;T;T;T;T

Polyphen

0.20

B;.;B;B;.

Vest4

0.29

MutPred

0.52

Loss of ubiquitination at K1683 (P = 0.0877);.;.;.;.;

MVP

0.86

MPC

0.50

ClinPred

0.10

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.16

gMVP

0.46

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