rs782352193

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_001110556.2(FLNA):c.5069C>T(p.Thr1690Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,211,240 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. T1690T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 0 hem., cov: 27)

Exomes 𝑓: 0.000010 ( 0 hom. 6 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 8.00

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: Likely_benign. The variant received -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.801

BP6

Variant X-154354973-G-A is Benign according to our data. Variant chrX-154354973-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 591330.

BS2

High Hemizygotes in GnomAdExome4 at 6 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2 link	c.5069C>T	p.Thr1690Met	missense_variant	Exon 31 of 48	ENST00000369850.10	NP_001104026.1	P21333-1Q60FE5Q6NXF2
FLNA	NM_001456.4 link	c.5045C>T	p.Thr1682Met	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.5069C>T	p.Thr1690Met	missense_variant	Exon 31 of 48	1	NM_001110556.2	ENSP00000358866.3		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.00000882

AC:

AN:

113397

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000920

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

GnomAD2 exomes

AF:

0.0000165

AC:

AN:

181482

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000731

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000738

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1097790

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26400

American (AMR)

AF:

0.0000852

AC:

AN:

35200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000369

AC:

AN:

54146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40189

Middle Eastern (MID)

AF:

0.000484

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

842037

Other (OTH)

AF:

0.0000434

AC:

AN:

46090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

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:

0.00000881

AC:

AN:

113450

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35600

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31352

American (AMR)

AF:

0.0000919

AC:

AN:

10883

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2662

East Asian (EAS)

AF:

0.00

AC:

AN:

3574

South Asian (SAS)

AF:

0.00

AC:

AN:

2847

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53362

Other (OTH)

AF:

0.00

AC:

AN:

1564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Apr 16, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

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

Benign:1

Oct 03, 2023

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

0.15

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

D;.;.;.;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D;.;D;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.80

D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.1

M;.;.;.;.

PhyloP100

8.0

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-4.1

D;.;D;D;.

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

D;.;D;D;.

Sift4G

Uncertain

0.014

D;D;D;D;D

Polyphen

1.0

D;.;D;D;.

Vest4

0.70

MutPred

0.68

Loss of phosphorylation at T1690 (P = 0.0773);.;.;.;.;

MVP

0.98

MPC

1.4

ClinPred

0.79

GERP RS

5.4

PromoterAI

0.041

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.74

gMVP

0.85

Mutation Taster

=257/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over