3-179576700-G-A

Position:

chr3-179576700-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS2

The NM_004301.5(ACTL6A):c.652G>A(p.Val218Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000462 in 1,613,560 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00050 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

ACTL6A
NM_004301.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 4.19

Variant links:

Genes affected

ACTL6A (HGNC:24124): (actin like 6A) This gene encodes a family member of actin-related proteins (ARPs), which share significant amino acid sequence identity to conventional actins. Both actins and ARPs have an actin fold, which is an ATP-binding cleft, as a common feature. The ARPs are involved in diverse cellular processes, including vesicular transport, spindle orientation, nuclear migration and chromatin remodeling. This gene encodes a 53 kDa subunit protein of the BAF (BRG1/brm-associated factor) complex in mammals, which is functionally related to SWI/SNF complex in S. cerevisiae and Drosophila; the latter is thought to facilitate transcriptional activation of specific genes by antagonizing chromatin-mediated transcriptional repression. Together with beta-actin, it is required for maximal ATPase activity of BRG1, and for the association of the BAF complex with chromatin/matrix. Three transcript variants that encode two different protein isoforms have been described. [provided by RefSeq, Jul 2008]

ACTL6A links:

ACTL6A (HGNC:):

ACTL6A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTL6A. . Gene score misZ 2.9398 (greater than the threshold 3.09). Trascript score misZ 3.625 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, syndromic intellectual disability, ACTL6A-related BAFopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.008425951).

BP6

Variant 3-179576700-G-A is Benign according to our data. Variant chr3-179576700-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2207126.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTL6A	NM_004301.5 linkuse as main transcript	c.652G>A	p.Val218Ile	missense_variant	7/14	ENST00000429709.7	NP_004292.1	O96019-1
ACTL6A	NM_177989.4 linkuse as main transcript	c.526G>A	p.Val176Ile	missense_variant	7/14		NP_817126.1	O96019-2
ACTL6A	NM_178042.4 linkuse as main transcript	c.526G>A	p.Val176Ile	missense_variant	7/14		NP_829888.1	O96019-2
LOC124909462	XR_007096181.1 linkuse as main transcript	n.85+62C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTL6A	ENST00000429709.7 linkuse as main transcript	c.652G>A	p.Val218Ile	missense_variant	7/14	1	NM_004301.5	ENSP00000397552.2		O96019-1

Frequencies

GnomAD3 genomes

AF:

0.000500

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.000510

AC:

128

AN:

251150

Hom.:

AF XY:

0.000486

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00556

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000458

AC:

670

AN:

1461340

Hom.:

Cov.:

AF XY:

0.000472

AC XY:

343

AN XY:

726992

show subpopulations

Gnomad4 AFR exome

AF:

0.000628

Gnomad4 AMR exome

AF:

0.000939

Gnomad4 ASJ exome

AF:

0.00524

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000345

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000499

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.000465

Hom.:

Bravo

AF:

0.000510

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000305

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000771

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2021

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. -

ACTL6A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 27, 2020

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

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.43

DEOGEN2

Benign

0.39

T;.;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.71

T;.;T

M_CAP

Benign

0.074

MetaRNN

Benign

0.0084

T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

-0.015

N;.;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.27

N;N;N

REVEL

Benign

0.23

Sift

Benign

0.82

T;T;T

Sift4G

Benign

0.80

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.16

MVP

0.31

MPC

0.73

ClinPred

0.0085

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.014

gMVP

0.098

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over