rs782549299

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001110556.2(FLNA):c.1238C>T(p.Thr413Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000043 in 1,209,312 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T413T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 1 hem., cov: 25)

Exomes 𝑓: 0.000036 ( 0 hom. 12 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.548

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

periventricular nodular heterotopia
Inheritance: AD, XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
frontometaphyseal dysplasia 1
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
genetic developmental and epileptic encephalopathy
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
heterotopia, periventricular, X-linked dominant
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Melnick-Needles syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
otopalatodigital syndrome type 2
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
terminal osseous dysplasia-pigmentary defects syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
cardiac valvular dysplasia, X-linked
Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
frontometaphyseal dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital short bowel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
otopalatodigital syndrome type 1
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked Ehlers-Danlos syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
familial thoracic aortic aneurysm and aortic dissection
Inheritance: XL Classification: LIMITED Submitted by: ClinGen

FLNA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21709329).

BP6

Variant X-154366215-G-A is Benign according to our data. Variant chrX-154366215-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211010.

BS2

High Hemizygotes in GnomAdExome4 at 12 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2 link	c.1238C>T	p.Thr413Met	missense_variant	Exon 9 of 48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4 link	c.1238C>T	p.Thr413Met	missense_variant	Exon 9 of 47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10 link	c.1238C>T	p.Thr413Met	missense_variant	Exon 9 of 48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

112243

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000972

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000932

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:

0.000151

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000500

AC:

AN:

180172

AF XY:

0.0000300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.000135

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000620

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000365

AC:

AN:

1097069

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

362951

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.0000852

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19378

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39506

Middle Eastern (MID)

AF:

0.000484

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.0000380

AC:

AN:

842021

Other (OTH)

AF:

0.0000651

AC:

AN:

46080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000107

AC:

AN:

112243

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34437

show subpopulations

African (AFR)

AF:

0.0000972

AC:

AN:

30880

American (AMR)

AF:

0.0000932

AC:

AN:

10735

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3560

South Asian (SAS)

AF:

0.00

AC:

AN:

2741

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6179

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.000151

AC:

AN:

53063

Other (OTH)

AF:

0.00

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

May 15, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 29, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Jul 11, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T413M variant (also known as c.1238C>T), located in coding exon 8 of the FLNA gene, results from a C to T substitution at nucleotide position 1238. The threonine at codon 413 is replaced by methionine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and methionine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant

Benign:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 09, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21520333) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Uncertain

0.52

D;.;.;.;.

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.81

T;T;.;T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.22

T;T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.2

L;.;L;L;.

PhyloP100

0.55

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.4

N;.;N;N;.

REVEL

Benign

0.092

Sift

Benign

0.24

T;.;T;T;.

Sift4G

Benign

0.10

T;T;T;T;T

Polyphen

0.17

B;.;B;B;.

Vest4

0.25

MutPred

0.42

Loss of catalytic residue at T413 (P = 0.0172);.;Loss of catalytic residue at T413 (P = 0.0172);Loss of catalytic residue at T413 (P = 0.0172);.;

MVP

0.76

MPC

0.79

ClinPred

0.017

GERP RS

0.0043

PromoterAI

0.025

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.032

gMVP

0.29

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over