X-154371181-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001110556.2(FLNA):c.65A>G(p.Asp22Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,194,162 control chromosomes in the GnomAD database, including 1 homozygotes. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. D22H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., 11 hem., cov: 25)

Exomes 𝑓: 0.000058 ( 1 hom. 15 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.02

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.116043776).

BP6

Variant X-154371181-T-C is Benign according to our data. Variant chrX-154371181-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 391884.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000302 (34/112410) while in subpopulation AMR AF = 0.00268 (29/10841). AF 95% confidence interval is 0.00191. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 11 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNA	NM_001110556.2	MANE Select	c.65A>G	p.Asp22Gly	missense	Exon 2 of 48	NP_001104026.1
	FLNA	NM_001456.4		c.65A>G	p.Asp22Gly	missense	Exon 2 of 47	NP_001447.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLNA	ENST00000369850.10	TSL:1 MANE Select	c.65A>G	p.Asp22Gly	missense	Exon 2 of 48	ENSP00000358866.3
FLNA	ENST00000360319.9	TSL:1	c.65A>G	p.Asp22Gly	missense	Exon 1 of 46	ENSP00000353467.4
FLNA	ENST00000369856.8	TSL:1	c.-17A>G		5_prime_UTR	Exon 1 of 47	ENSP00000358872.4

Frequencies

GnomAD3 genomes

AF:

0.000303

AC:

AN:

112360

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

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:

0.00265

GnomAD2 exomes

AF:

0.0000343

AC:

AN:

145796

AF XY:

0.0000216

show subpopulations

Gnomad AFR exome

AF:

0.000212

Gnomad AMR exome

AF:

0.000125

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:

0.0000582

AC:

AN:

1081752

Hom.:

Cov.:

AF XY:

0.0000425

AC XY:

AN XY:

352676

show subpopulations

African (AFR)

AF:

0.0000382

AC:

AN:

26209

American (AMR)

AF:

0.000548

AC:

AN:

32819

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19020

East Asian (EAS)

AF:

0.00

AC:

AN:

29604

South Asian (SAS)

AF:

0.00

AC:

AN:

52094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38205

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3764

European-Non Finnish (NFE)

AF:

0.0000371

AC:

AN:

834655

Other (OTH)

AF:

0.000286

AC:

AN:

45382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

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:

0.000302

AC:

AN:

112410

Hom.:

Cov.:

AF XY:

0.000318

AC XY:

AN XY:

34632

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31012

American (AMR)

AF:

0.00268

AC:

AN:

10841

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3532

South Asian (SAS)

AF:

0.00

AC:

AN:

2704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53065

Other (OTH)

AF:

0.00262

AC:

AN:

1528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.00

Hom.:

Bravo

AF:

0.000650

ExAC

AF:

0.0000171

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.36

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.84

MutationAssessor

Benign

-0.090

PhyloP100

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.31

REVEL

Benign

0.10

Sift

Benign

0.18

Sift4G

Benign

0.23

Polyphen

0.0

Vest4

0.091

MutPred

0.28

Gain of catalytic residue at G20 (P = 0.0891)

MVP

0.72

MPC

1.8

ClinPred

0.015

GERP RS

3.4

PromoterAI

-0.028

Neutral

(source)

Varity_R

0.17

gMVP

0.77

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over