X-154349490-C-T

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.7628G>A(p.Cys2543Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,211,541 control chromosomes in the GnomAD database, including 1 homozygotes. There are 51 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. C2543F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00025 ( 1 hom., 8 hem., cov: 26)

Exomes 𝑓: 0.00013 ( 0 hom. 43 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5

Conservation

PhyloP100: 0.127

Publications

0 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=0.09588739).

BP6

Variant X-154349490-C-T is Benign according to our data. Variant chrX-154349490-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 392335.

BS2

High Hemizygotes in GnomAd4 at 8 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2 link	c.7628G>A	p.Cys2543Tyr	missense_variant	Exon 47 of 48	ENST00000369850.10	NP_001104026.1	P21333-1Q60FE5Q6NXF2
FLNA	NM_001456.4 link	c.7604G>A	p.Cys2535Tyr	missense_variant	Exon 46 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.7628G>A	p.Cys2543Tyr	missense_variant	Exon 47 of 48	1	NM_001110556.2	ENSP00000358866.3		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.000246

AC:

AN:

113810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000318

Gnomad AMI

AF:

0.00146

Gnomad AMR

AF:

0.000183

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:

0.000412

Gnomad OTH

AF:

0.00129

GnomAD2 exomes

AF:

0.0000661

AC:

AN:

181498

AF XY:

0.0000592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000135

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000135

AC:

148

AN:

1097731

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

363291

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26402

American (AMR)

AF:

0.0000568

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.00

AC:

AN:

54145

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.000165

AC:

139

AN:

841996

Other (OTH)

AF:

0.000130

AC:

AN:

46082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.000246

AC:

AN:

113810

Hom.:

Cov.:

AF XY:

0.000223

AC XY:

AN XY:

35926

show subpopulations

African (AFR)

AF:

0.0000318

AC:

AN:

31410

American (AMR)

AF:

0.000183

AC:

AN:

10914

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2664

East Asian (EAS)

AF:

0.00

AC:

AN:

3632

South Asian (SAS)

AF:

0.00

AC:

AN:

2864

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6409

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

53444

Other (OTH)

AF:

0.00129

AC:

AN:

1549

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.000227

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FLNA: BP4, BS2 -

Jun 25, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 15, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 18, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 21, 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.7604G>A; p.Cys2535Tyr variant (rs201762017, ClinVar Variation ID: 392335), is reported in the literature in one individual with aortic root dilation (Rashed 2022). This variant is found in the general population with an overall allele frequency of 0.007 % (15 / 203,700 alleles, including 5 hemizygotes) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.153). Due to limited information, the clinical significance of the p.Cys2535Tyr variant is uncertain at this time. References: Rashed ER et al. Cardiovascular manifestations of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders. Vasc Med. 2022 Jun;27(3):283-289. PMID: 35000503. -

Melnick-Needles syndrome;C0262436:Cardiac valvular dysplasia, X-linked;C0265251:Oto-palato-digital syndrome, type I;C1844696:Oto-palato-digital syndrome, type II;C1845902:FG syndrome 2;C1846129:Terminal osseous dysplasia-pigmentary defects syndrome;C1848213:Heterotopia, periventricular, X-linked dominant;C2746068:Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked;C4281559:Frontometaphyseal dysplasia 1

Uncertain:1

Dec 28, 2017

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Sep 04, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FLNA c.7628G>A (p.Cys2543Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 1211541 control chromosomes, predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote and 51 hemizygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 576 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNA causing Periventricular Nodular Heterotopia phenotype (3.1e-07). c.7628G>A has been reported in the literature in at least an individual affected with cerebral vein thrombosis (Kramer_2023). This report does not provide unequivocal conclusions about association of the variant with Periventricular Nodular Heterotopia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 37175682). ClinVar contains an entry for this variant (Variation ID: 392335). Based on the evidence outlined above, the variant was classified as likely benign. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Aug 23, 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 21, 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

0.075

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.34

T;.;.;.;.

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.83

T;T;.;T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.096

T;T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.0

N;.;.;.;.

PhyloP100

0.13

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.95

N;.;N;N;.

REVEL

Benign

0.15

Sift

Benign

0.033

D;.;D;D;.

Sift4G

Benign

0.061

T;T;T;T;T

Polyphen

0.12

B;.;B;B;.

Vest4

0.12

MVP

0.65

MPC

0.86

ClinPred

0.032

GERP RS

-0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.65

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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