X-154365465-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001110556.2(FLNA):c.1451G>A(p.Arg484Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000413 in 1,210,301 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R484W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000041 ( 0 hom. 15 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:3

Conservation

PhyloP100: 3.35

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 -16 ACMG points.

BP6

Variant X-154365465-C-T is Benign according to our data. Variant chrX-154365465-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 213520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000041 (45/1097234) while in subpopulation MID AF = 0.00145 (6/4133). AF 95% confidence interval is 0.000631. There are 0 homozygotes in GnomAdExome4. There are 15 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 15 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2 link	c.1451G>A	p.Arg484Gln	missense_variant	Exon 10 of 48	ENST00000369850.10	NP_001104026.1	P21333-1Q60FE5Q6NXF2
FLNA	NM_001456.4 link	c.1451G>A	p.Arg484Gln	missense_variant	Exon 10 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.1451G>A	p.Arg484Gln	missense_variant	Exon 10 of 48	1	NM_001110556.2	ENSP00000358866.3		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000442

AC:

AN:

113067

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000376

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

GnomAD2 exomes

AF:

0.0000779

AC:

AN:

179740

AF XY:

0.0000898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000732

Gnomad ASJ exome

AF:

0.000136

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000100

Gnomad OTH exome

AF:

0.000453

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1097234

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

363116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26399

American (AMR)

AF:

0.0000568

AC:

AN:

35197

Ashkenazi Jewish (ASJ)

AF:

0.000155

AC:

AN:

19376

East Asian (EAS)

AF:

0.00

AC:

AN:

30196

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39763

Middle Eastern (MID)

AF:

0.00145

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.0000321

AC:

AN:

841978

Other (OTH)

AF:

0.000130

AC:

AN:

46062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.0000442

AC:

AN:

113067

Hom.:

Cov.:

AF XY:

0.0000284

AC XY:

AN XY:

35223

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31169

American (AMR)

AF:

0.00

AC:

AN:

10815

Ashkenazi Jewish (ASJ)

AF:

0.000376

AC:

AN:

2658

East Asian (EAS)

AF:

0.00

AC:

AN:

3575

South Asian (SAS)

AF:

0.00

AC:

AN:

2817

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6315

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000751

AC:

AN:

53266

Other (OTH)

AF:

0.00

AC:

AN:

1529

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.000174

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000580

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Heterotopia, periventricular, X-linked dominant

Pathogenic:1

Oct 11, 2020

Sezerman Lab, Dept of Biostatistics and Bioinformatics, Acibadem Mehmet Ali Aydinlar University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The p.Arg484Gln variant in FLNA has been reported in two Turkish brothers (age of onset: 16 and 11; with healthy parents and grandparents) with occipital lobe epilepsy and epileptic status in sleep. They are diagnosed as periventricular nodular heterotopia (PVNH), which is a cell migration disorder. Heterozygous mother is asymptomatic, and healthy father carries the reference allele. Generally, heterozygous females carrying PVNH-related missense mutations have mild or no symptoms as in the mother. This is the reason of the presence of this variant (rs782371735) in the population databases (e.g. ExAC 0.009%). On the other hand, only a few males (<40) can survive, and they should have compensating mechanisms for the function of FLNA. Therefore, we investigated the etiology of the disease by observing the impact of PVNH-related FLNA mutations found in the liveborn males on the structure and dynamics of FLNA protein via molecular dynamics (MD) simulations. For the p.Arg484Gln variant, MD studies showed that the mutation does not lead to a general misfolding or permanent loss of function. Instead, it may cause a temporary dysfunction since we observed significant changes in the fluctuations (higher), solvent-accessible surface area (lower), conformational space and local interactions (i.e. H-bonds and salt bridges within 10 Ã… of the mutation site) in the half of the MD simulations. This event might lead to formation of nodules in the periventricular region and might also compensate the cell migration function. Thus, the males who have this variant can survive with the only copy of mutated FLNA. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Jan 20, 2022

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 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Aug 12, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31625567) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.76

D;.;.;.;.

FATHMM_MKL

Benign

0.75

LIST_S2

Pathogenic

0.99

D;D;.;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Uncertain

0.63

D;D;D;D;D

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.7

M;.;M;M;.

PhyloP100

3.4

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.8

D;.;D;D;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.0020

D;.;D;D;.

Sift4G

Uncertain

0.015

D;D;D;D;D

Polyphen

1.0

D;.;D;D;.

Vest4

0.44

MVP

0.92

MPC

1.5

ClinPred

0.34

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.79

gMVP

0.53

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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