rs373089783

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.5342A>G(p.Asn1781Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,210,332 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 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).

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 0 hem., cov: 26)

Exomes 𝑓: 0.000047 ( 0 hom. 15 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.56

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=0.16465077).

BP6

Variant X-154354455-T-C is Benign according to our data. Variant chrX-154354455-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213477.

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.5342A>G	p.Asn1781Ser	missense_variant	Exon 33 of 48	ENST00000369850.10	NP_001104026.1
FLNA	NM_001456.4 link	c.5318A>G	p.Asn1773Ser	missense_variant	Exon 32 of 47		NP_001447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNA	ENST00000369850.10 link	c.5342A>G	p.Asn1781Ser	missense_variant	Exon 33 of 48	1	NM_001110556.2	ENSP00000358866.3

Frequencies

GnomAD3 genomes

AF:

0.0000707

AC:

AN:

113155

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000185

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:

0.0000939

Gnomad OTH

AF:

0.000656

GnomAD2 exomes

AF:

0.0000774

AC:

AN:

180796

AF XY:

0.0000595

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000111

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000474

AC:

AN:

1097177

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

362917

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26391

American (AMR)

AF:

0.000142

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000554

AC:

AN:

54138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000428

AC:

AN:

841771

Other (OTH)

AF:

0.000152

AC:

AN:

46075

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.0000707

AC:

AN:

113155

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35321

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31217

American (AMR)

AF:

0.000185

AC:

AN:

10826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3593

South Asian (SAS)

AF:

0.00

AC:

AN:

2832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6317

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000939

AC:

AN:

53262

Other (OTH)

AF:

0.000656

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.0000712

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000154

AC:

ExAC

AF:

0.0000745

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Oct 23, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS2

Feb 08, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 20, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

May 25, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.N1773S variant (also known as c.5318A>G), located in coding exon 31 of the FLNA gene, results from an A to G substitution at nucleotide position 5318. The asparagine at codon 1773 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well conserved in available 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.

not specified

Benign:1

Feb 05, 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.5342A>G (p.Asn1781Ser) results in a 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 5e-05 in 1210332 control chromosomes (gnomAD). The observed variant frequency is approximately 158 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNA causing Periventricular Nodular Heterotopia phenotype (3.1e-07), strongly suggesting that the variant is benign. c.5342A>G has been reported in the literature in at-least one individual affected with Epilepsy, however, authors classified this variant as unlikely to be pathogenic (example: DiFrancesco_2019). 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: 30986657). ClinVar contains an entry for this variant (Variation ID: 213477). Based on the evidence outlined above, the variant was classified as likely benign.

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

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.40

T;.;.;.;.

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.99

D;D;.;D;D

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.16

T;T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.1

L;.;.;.;.

PhyloP100

3.6

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.2

N;.;N;N;.

REVEL

Benign

0.26

Sift

Benign

0.38

T;.;T;T;.

Sift4G

Benign

0.54

T;T;T;T;T

Vest4

0.15

ClinPred

0.041

GERP RS

5.7

PromoterAI

-0.017

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.17

gMVP

0.47

Mutation Taster

=298/2

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