rs868064163

Positions:

chr3-179586552-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

The NM_004301.5(ACTL6A):c.1129C>T(p.Arg377Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000316 in 1,581,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ACTL6A
NM_004301.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.96

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.907

PP5

Variant 3-179586552-C-T is Pathogenic according to our data. Variant chr3-179586552-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 549661.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}. Variant chr3-179586552-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ACTL6A	NM_004301.5 linkuse as main transcript	c.1129C>T	p.Arg377Trp	missense_variant	13/14	ENST00000429709.7	NP_004292.1
ACTL6A	NM_177989.4 linkuse as main transcript	c.1003C>T	p.Arg335Trp	missense_variant	13/14		NP_817126.1
ACTL6A	NM_178042.4 linkuse as main transcript	c.1003C>T	p.Arg335Trp	missense_variant	13/14		NP_829888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTL6A	ENST00000429709.7 linkuse as main transcript	c.1129C>T	p.Arg377Trp	missense_variant	13/14	1	NM_004301.5	ENSP00000397552	P1	O96019-1

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151512

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000960

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000280

AC:

AN:

1430252

Hom.:

Cov.:

AF XY:

0.00000563

AC XY:

AN XY:

710996

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000271

Gnomad4 ASJ exome

AF:

0.0000394

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151512

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73896

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000960

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	literature only	OMIM	Mar 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -

Atrial septal defect;C0019294:Inguinal hernia;C0019322:Umbilical hernia;C0039070:Syncope;C0040485:Torticollis;C0426429:Broad nasal tip;C0426891:Broad thumb;C0454644:Delayed speech and language development;C0747085:Recurrent otitis media;C1845847:Coarse facial features;C1859077:Aplasia/Hypoplasia of the nails;C4023295:Cleft anterior mitral valve leaflet;C4317146:Gastroesophageal reflux

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Jun 11, 2017

This variant was identified as de novo in an individual with syndromic intellectual disability. In the same study, two additional unrelated affected subjects were also identified to have rare variation in this gene. The phenotypes of all 3 cases were felt to overlap with that of Coffin Siris syndrome, caused by mutations in genes associated with the BAF complex. ACTL6A encodes a BAF complex protein. -

BAFopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Immunology and Genetics Kaiserslautern

Jun 04, 2024

ACMG Criteria: PP3, PP5, PM2_P, PS3; Variant was found in heterozygous state, the ACTL6A gene was reported associated with BAFopathies (PMID: 34906496, PMID: 28649782, PMID: 3448540) -

ACTL6A-related BAFopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

D;.;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.8

D;D;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.86

MutPred

0.72

Loss of glycosylation at P374 (P = 0.0102);.;.;

MVP

0.83

MPC

2.0

ClinPred

1.0

GERP RS

5.0

Varity_R

0.81

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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