chr3-179576721-T-A

Position:

chr3-179576721-T-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBS1BS2

The NM_004301.5(ACTL6A):c.673T>A(p.Ser225Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,612,324 control chromosomes in the GnomAD database, including 177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.011 ( 14 hom., cov: 32)

Exomes 𝑓: 0.014 ( 163 hom. )

Consequence

ACTL6A
NM_004301.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 8.02

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 -13 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=0.009913951).

BP6

Variant 3-179576721-T-A is Benign according to our data. Variant chr3-179576721-T-A is described in ClinVar as [Benign]. Clinvar id is 1695087.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0136 (19806/1460016) while in subpopulation MID AF= 0.0184 (106/5762). AF 95% confidence interval is 0.0156. There are 163 homozygotes in gnomad4_exome. There are 9750 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1648 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTL6A	NM_004301.5 linkuse as main transcript	c.673T>A	p.Ser225Thr	missense_variant	7/14	ENST00000429709.7	NP_004292.1	O96019-1
ACTL6A	NM_177989.4 linkuse as main transcript	c.547T>A	p.Ser183Thr	missense_variant	7/14		NP_817126.1	O96019-2
ACTL6A	NM_178042.4 linkuse as main transcript	c.547T>A	p.Ser183Thr	missense_variant	7/14		NP_829888.1	O96019-2
LOC124909462	XR_007096181.1 linkuse as main transcript	n.85+41A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTL6A	ENST00000429709.7 linkuse as main transcript	c.673T>A	p.Ser225Thr	missense_variant	7/14	1	NM_004301.5	ENSP00000397552.2		O96019-1

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1647

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00766

Gnomad ASJ

AF:

0.0274

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0358

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0132

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.0118

AC:

2973

AN:

251078

Hom.:

AF XY:

0.0119

AC XY:

1622

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.00241

Gnomad AMR exome

AF:

0.00614

Gnomad ASJ exome

AF:

0.0240

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00575

Gnomad FIN exome

AF:

0.0305

Gnomad NFE exome

AF:

0.0137

Gnomad OTH exome

AF:

0.0139

GnomAD4 exome

AF:

0.0136

AC:

19806

AN:

1460016

Hom.:

163

Cov.:

AF XY:

0.0134

AC XY:

9750

AN XY:

726474

show subpopulations

Gnomad4 AFR exome

AF:

0.00206

Gnomad4 AMR exome

AF:

0.00620

Gnomad4 ASJ exome

AF:

0.0238

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00546

Gnomad4 FIN exome

AF:

0.0314

Gnomad4 NFE exome

AF:

0.0142

Gnomad4 OTH exome

AF:

0.0129

GnomAD4 genome

AF:

0.0108

AC:

1648

AN:

152308

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

866

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00250

Gnomad4 AMR

AF:

0.00765

Gnomad4 ASJ

AF:

0.0274

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.0358

Gnomad4 NFE

AF:

0.0132

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0129

Hom.:

Bravo

AF:

0.00889

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0123

AC:

106

ExAC

AF:

0.0115

AC:

1394

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0130

EpiControl

AF:

0.0143

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2024

ACTL6A: PP3, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

D;.;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.73

T;.;T

MetaRNN

Benign

0.0099

T;T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

1.4

L;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Pathogenic

0.71

Sift

Uncertain

0.017

D;D;D

Sift4G

Benign

0.15

T;T;T

Polyphen

0.61

P;.;.

Vest4

0.19

MPC

1.4

ClinPred

0.021

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.38

gMVP

0.61

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