rs201656372

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001110556.2(FLNA):c.2845G>A(p.Val949Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000248 in 1,203,992 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 90 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V949V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.00026 ( 0 hom. 85 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.09

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019046962).

BP6

Variant X-154361769-C-T is Benign according to our data. Variant chrX-154361769-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 5 XL,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110556.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	NM_001110556.2	MANE Select	c.2845G>A	p.Val949Ile	missense	Exon 20 of 48	NP_001104026.1
	FLNA	NM_001456.4		c.2845G>A	p.Val949Ile	missense	Exon 20 of 47	NP_001447.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLNA	ENST00000369850.10	TSL:1 MANE Select	c.2845G>A	p.Val949Ile	missense	Exon 20 of 48	ENSP00000358866.3
FLNA	ENST00000360319.9	TSL:1	c.2845G>A	p.Val949Ile	missense	Exon 19 of 46	ENSP00000353467.4
FLNA	ENST00000369856.8	TSL:1	c.2764G>A	p.Val922Ile	missense	Exon 19 of 47	ENSP00000358872.4

Frequencies

GnomAD3 genomes

AF:

0.000181

AC:

AN:

110703

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000329

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000954

Gnomad ASJ

AF:

0.00267

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000171

Gnomad OTH

AF:

0.00135

GnomAD2 exomes

AF:

0.000342

AC:

AN:

181409

AF XY:

0.000311

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000183

Gnomad ASJ exome

AF:

0.00469

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000259

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.000255

AC:

279

AN:

1093289

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

AN XY:

358855

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26305

American (AMR)

AF:

0.000170

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00465

AC:

AN:

19360

East Asian (EAS)

AF:

0.00

AC:

AN:

30189

South Asian (SAS)

AF:

0.00

AC:

AN:

54024

European-Finnish (FIN)

AF:

0.0000248

AC:

AN:

40258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

0.000171

AC:

143

AN:

837890

Other (OTH)

AF:

0.000827

AC:

AN:

45946

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:

0.000181

AC:

AN:

110703

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

AN XY:

32913

show subpopulations

African (AFR)

AF:

0.0000329

AC:

AN:

30441

American (AMR)

AF:

0.0000954

AC:

AN:

10487

Ashkenazi Jewish (ASJ)

AF:

0.00267

AC:

AN:

2619

East Asian (EAS)

AF:

0.00

AC:

AN:

3534

South Asian (SAS)

AF:

0.00

AC:

AN:

2526

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.000171

AC:

AN:

52715

Other (OTH)

AF:

0.00135

AC:

AN:

1486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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:

0.000314

Hom.:

Bravo

AF:

0.000310

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000381

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Familial thoracic aortic aneurysm and aortic dissection (1)

FLNA-related disorder (1)

Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.030

MetaRNN

Benign

0.019

MetaSVM

Uncertain

0.45

MutationAssessor

Benign

1.7

PhyloP100

4.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.79

REVEL

Uncertain

0.43

Sift

Benign

0.081

Sift4G

Uncertain

0.060

Polyphen

0.86

Vest4

0.27

MVP

0.89

MPC

0.91

ClinPred

0.095

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.27

gMVP

0.28

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over