rs200679107

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_001110556.2(FLNA):c.2609A>G(p.His870Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,209,590 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 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. H870Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.000068 ( 0 hom. 28 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:4

Conservation

PhyloP100: 7.94

Publications

1 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 -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when Cadd, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.052993834).

BP6

Variant X-154362289-T-C is Benign according to our data. Variant chrX-154362289-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 587846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000134 (15/111894) while in subpopulation SAS AF = 0.00224 (6/2678). AF 95% confidence interval is 0.000975. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 7 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2 link	c.2609A>G	p.His870Arg	missense_variant	Exon 18 of 48	ENST00000369850.10	NP_001104026.1	P21333-1Q60FE5Q6NXF2
FLNA	NM_001456.4 link	c.2609A>G	p.His870Arg	missense_variant	Exon 18 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.2609A>G	p.His870Arg	missense_variant	Exon 18 of 48	1	NM_001110556.2	ENSP00000358866.3		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.000134

AC:

AN:

111840

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000260

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000941

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00223

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000773

AC:

AN:

181221

AF XY:

0.0000741

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000683

AC:

AN:

1097696

Hom.:

Cov.:

AF XY:

0.0000771

AC XY:

AN XY:

363310

show subpopulations

African (AFR)

AF:

0.000606

AC:

AN:

26403

American (AMR)

AF:

0.0000284

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00103

AC:

AN:

54145

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40068

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

842055

Other (OTH)

AF:

0.0000434

AC:

AN:

46091

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.000134

AC:

AN:

111894

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

AN XY:

34090

show subpopulations

African (AFR)

AF:

0.000260

AC:

AN:

30818

American (AMR)

AF:

0.0000939

AC:

AN:

10645

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3529

South Asian (SAS)

AF:

0.00224

AC:

AN:

2678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6187

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52968

Other (OTH)

AF:

0.00

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000226

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.000552

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Feb 27, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Feb 12, 2018

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

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FLNA-related disorder

Benign:1

May 19, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.;.;.;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;.;D;D

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.053

T;T;T;T;T

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.0

M;.;M;M;.

PhyloP100

7.9

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-6.0

D;.;D;D;.

REVEL

Pathogenic

0.83

Sift

Benign

0.034

D;.;D;D;.

Sift4G

Uncertain

0.044

D;D;D;D;T

Polyphen

0.24

B;.;D;D;.

Vest4

0.36

MVP

0.97

MPC

1.6

ClinPred

0.30

GERP RS

4.9

Varity_R

0.91

gMVP

0.65

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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