NM_001110556.2:c.3246G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001110556.2(FLNA):c.3246G>A(p.Ala1082Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,208,168 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.000027 ( 0 hom. 14 hem. )

Consequence

FLNA
NM_001110556.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.51

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant X-154360549-C-T is Benign according to our data. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360549-C-T is described in CliVar as Likely_benign. Clinvar id is 389814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.51 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 2 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNA	NM_001110556.2 link	c.3246G>A	p.Ala1082Ala	synonymous_variant	Exon 22 of 48	ENST00000369850.10	NP_001104026.1	P21333-1Q60FE5Q6NXF2
FLNA	NM_001456.4 link	c.3246G>A	p.Ala1082Ala	synonymous_variant	Exon 22 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.3246G>A	p.Ala1082Ala	synonymous_variant	Exon 22 of 48	1	NM_001110556.2	ENSP00000358866.3		P21333-1

Frequencies

GnomAD3 genomes

AF:

0.0000265

AC:

AN:

113105

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000641

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000116

AC:

AN:

173158

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000261

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1095063

Hom.:

Cov.:

AF XY:

0.0000387

AC XY:

AN XY:

361725

show subpopulations

African (AFR)

AF:

0.000227

AC:

AN:

26393

American (AMR)

AF:

0.00

AC:

AN:

35158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19341

East Asian (EAS)

AF:

0.00

AC:

AN:

30186

South Asian (SAS)

AF:

0.0000555

AC:

AN:

54100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37978

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.0000214

AC:

AN:

841763

Other (OTH)

AF:

0.0000652

AC:

AN:

46010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.0000265

AC:

AN:

113105

Hom.:

Cov.:

AF XY:

0.0000567

AC XY:

AN XY:

35245

show subpopulations

African (AFR)

AF:

0.0000641

AC:

AN:

31207

American (AMR)

AF:

0.00

AC:

AN:

10843

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3570

South Asian (SAS)

AF:

0.00

AC:

AN:

2793

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53248

Other (OTH)

AF:

0.00

AC:

AN:

1531

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Oct 20, 2019

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 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 09, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FLNA-related disorder

Benign:1

Mar 25, 2022

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

BayesDel_noAF

Benign

-0.49

CADD

Benign

1.8

(source)

DANN

Benign

0.69

PhyloP100

-1.5

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

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