X-154348893-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP3BP6_Moderate

The NM_001110556.2(FLNA):c.7900G>C(p.Asp2634His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,552 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. D2634N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.84

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.808

BP6

Variant X-154348893-C-G is Benign according to our data. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154348893-C-G is described in CliVar as Likely_benign. Clinvar id is 533571.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2 link	c.7900G>C	p.Asp2634His	missense_variant	Exon 48 of 48	ENST00000369850.10	NP_001104026.1	P21333-1Q60FE5Q6NXF2
FLNA	NM_001456.4 link	c.7876G>C	p.Asp2626His	missense_variant	Exon 47 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.7900G>C	p.Asp2634His	missense_variant	Exon 48 of 48	1	NM_001110556.2	ENSP00000358866.3		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000187

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

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096552

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26373

American (AMR)

AF:

0.0000284

AC:

AN:

35160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19341

East Asian (EAS)

AF:

0.00

AC:

AN:

30166

South Asian (SAS)

AF:

0.00

AC:

AN:

54072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40121

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841154

Other (OTH)

AF:

0.00

AC:

AN:

46037

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000178

AC:

AN:

112112

Hom.:

Cov.:

AF XY:

0.0000583

AC XY:

AN XY:

34300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30891

American (AMR)

AF:

0.000187

AC:

AN:

10700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3554

South Asian (SAS)

AF:

0.00

AC:

AN:

2722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6167

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52996

Other (OTH)

AF:

0.00

AC:

AN:

1520

Age Distribution

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

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

D;.;.;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;.;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.81

D;D;D;D;D

MetaSVM

Uncertain

0.58

MutationAssessor

Pathogenic

3.5

H;.;.;.;.

PhyloP100

7.8

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-5.0

D;.;D;D;.

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0020

D;.;D;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;.;P;P;.

Vest4

0.53

MutPred

0.73

Gain of disorder (P = 0.0849);.;.;.;.;

MVP

0.86

MPC

1.6

ClinPred

0.99

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.87

gMVP

0.81

Mutation Taster

=90/10

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over