3-179573467-C-T

Position:

chr3-179573467-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM5PP2BP4BS2

The NM_004301.5(ACTL6A):c.376C>T(p.Pro126Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000078 in 1,539,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P126L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

ACTL6A
NM_004301.5 missense, splice_region

Scores

Splicing: ADA: 0.1841

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.91

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-179573468-C-T is described in Lovd as [Likely_pathogenic].

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=0.293604).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTL6A	NM_004301.5 linkuse as main transcript	c.376C>T	p.Pro126Ser	missense_variant, splice_region_variant	4/14	ENST00000429709.7	NP_004292.1	O96019-1
ACTL6A	NM_177989.4 linkuse as main transcript	c.250C>T	p.Pro84Ser	missense_variant, splice_region_variant	4/14		NP_817126.1	O96019-2
ACTL6A	NM_178042.4 linkuse as main transcript	c.250C>T	p.Pro84Ser	missense_variant, splice_region_variant	4/14		NP_829888.1	O96019-2
LOC124909462	XR_007096181.1 linkuse as main transcript	n.86-1697G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTL6A	ENST00000429709.7 linkuse as main transcript	c.376C>T	p.Pro126Ser	missense_variant, splice_region_variant	4/14	1	NM_004301.5	ENSP00000397552.2		O96019-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151332

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000533

AC:

AN:

187684

Hom.:

AF XY:

0.00000968

AC XY:

AN XY:

103270

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000721

AC:

AN:

1387740

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

688674

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000922

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151332

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73862

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:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2024

The c.376C>T (p.P126S) alteration is located in exon 4 (coding exon 4) of the ACTL6A gene. This alteration results from a C to T substitution at nucleotide position 376, causing the proline (P) at amino acid position 126 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Benign

0.51

DEOGEN2

Uncertain

0.60

D;.;.

Eigen

Benign

0.051

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

D;.;D

M_CAP

Benign

0.053

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

1.3

L;.;.

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.1

N;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.78

T;T;T

Sift4G

Benign

0.66

T;T;T

Polyphen

0.0040

B;.;.

Vest4

0.28

MutPred

0.71

Loss of sheet (P = 0.0817);.;.;

MVP

0.59

MPC

0.89

ClinPred

0.23

GERP RS

5.6

Varity_R

0.20

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.18

dbscSNV1_RF

Benign

0.42

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