rs200130356

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001110556.2(FLNA):c.4451A>G(p.Gln1484Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00138 in 1,209,895 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 558 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1484H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., 26 hem., cov: 24)

Exomes 𝑓: 0.0014 ( 0 hom. 532 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:16

Conservation

PhyloP100: 4.99

Publications

4 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, Illumina, Labcorp Genetics (formerly Invitae), G2P
intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Melnick-Needles syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
otopalatodigital syndrome type 2
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
terminal osseous dysplasia-pigmentary defects syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, 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: Unknown 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0398449).

BP6

Variant X-154359007-T-C is Benign according to our data. Variant chrX-154359007-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190194.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000844 (95/112552) while in subpopulation NFE AF = 0.00156 (83/53128). AF 95% confidence interval is 0.00129. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 26 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.4451A>G	p.Gln1484Arg	missense	Exon 26 of 48	NP_001104026.1	P21333-1
	FLNA	NM_001456.4		c.4451A>G	p.Gln1484Arg	missense	Exon 26 of 47	NP_001447.2	P21333-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLNA	ENST00000369850.10	TSL:1 MANE Select	c.4451A>G	p.Gln1484Arg	missense	Exon 26 of 48	ENSP00000358866.3	P21333-1
FLNA	ENST00000360319.9	TSL:1	c.4451A>G	p.Gln1484Arg	missense	Exon 25 of 46	ENSP00000353467.4	P21333-2
FLNA	ENST00000369856.8	TSL:1	c.4370A>G	p.Gln1457Arg	missense	Exon 25 of 47	ENSP00000358872.4	Q60FE5

Frequencies

GnomAD3 genomes

AF:

0.000844

AC:

AN:

112497

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000933

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000726

Gnomad FIN

AF:

0.000161

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00102

AC:

186

AN:

181561

AF XY:

0.00115

show subpopulations

Gnomad AFR exome

AF:

0.000404

Gnomad AMR exome

AF:

0.0000730

Gnomad ASJ exome

AF:

0.000268

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000315

Gnomad NFE exome

AF:

0.00177

Gnomad OTH exome

AF:

0.00112

GnomAD4 exome

AF:

0.00144

AC:

1578

AN:

1097343

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

532

AN XY:

363145

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26396

American (AMR)

AF:

0.000114

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00129

AC:

AN:

54145

European-Finnish (FIN)

AF:

0.000754

AC:

AN:

39808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4114

European-Non Finnish (NFE)

AF:

0.00167

AC:

1406

AN:

842005

Other (OTH)

AF:

0.00139

AC:

AN:

46079

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

132

197

263

329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.000844

AC:

AN:

112552

Hom.:

Cov.:

AF XY:

0.000749

AC XY:

AN XY:

34734

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

31049

American (AMR)

AF:

0.0000932

AC:

AN:

10732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3579

South Asian (SAS)

AF:

0.000728

AC:

AN:

2746

European-Finnish (FIN)

AF:

0.000161

AC:

AN:

6215

Middle Eastern (MID)

AF:

0.00917

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00156

AC:

AN:

53128

Other (OTH)

AF:

0.00

AC:

AN:

1544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.00114

Hom.:

Bravo

AF:

0.000718

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00277

AC:

ESP6500AA

AF:

0.000279

AC:

ESP6500EA

AF:

0.00152

AC:

ExAC

AF:

0.00127

AC:

154

EpiCase

AF:

0.00153

EpiControl

AF:

0.00136

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (4)

Heterotopia, periventricular, X-linked dominant (2)

Aortic dilatation (1)

Connective tissue disorder (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

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

Thrombocytopenia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.040

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.84

PhyloP100

5.0

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.54

Sift

Benign

0.12

Sift4G

Benign

0.33

Polyphen

0.060

Vest4

0.48

MVP

0.96

MPC

0.55

ClinPred

0.026

GERP RS

5.7

Varity_R

0.46

gMVP

0.52

Mutation Taster

=83/17

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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