rs761055025

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P126L) has been classified as Uncertain significance.

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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

ACTL6A-related BAFopathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
syndromic intellectual disability
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Illumina
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACTL6A links:

LOC124909462 (HGNC:):

LOC124909462 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.293604).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004301.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTL6A	NM_004301.5	MANE Select	c.376C>T	p.Pro126Ser	missense splice_region	Exon 4 of 14	NP_004292.1	O96019-1
ACTL6A	NM_177989.4		c.250C>T	p.Pro84Ser	missense splice_region	Exon 4 of 14	NP_817126.1	O96019-2
ACTL6A	NM_178042.4		c.250C>T	p.Pro84Ser	missense splice_region	Exon 4 of 14	NP_829888.1	O96019-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTL6A	ENST00000429709.7	TSL:1 MANE Select	c.376C>T	p.Pro126Ser	missense splice_region	Exon 4 of 14	ENSP00000397552.2	O96019-1
ACTL6A	ENST00000450518.6	TSL:1	c.250C>T	p.Pro84Ser	missense splice_region	Exon 4 of 14	ENSP00000394014.2	O96019-2
ACTL6A	ENST00000879836.1		c.370C>T	p.Pro124Ser	missense splice_region	Exon 4 of 14	ENSP00000549895.1

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

GnomAD2 exomes

AF:

0.00000533

AC:

AN:

187684

AF XY:

0.00000968

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 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

African (AFR)

AF:

0.00

AC:

AN:

28768

American (AMR)

AF:

0.00

AC:

AN:

27812

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24462

East Asian (EAS)

AF:

0.00

AC:

AN:

35448

South Asian (SAS)

AF:

0.00

AC:

AN:

70732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52994

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5600

European-Non Finnish (NFE)

AF:

0.00000922

AC:

AN:

1084362

Other (OTH)

AF:

0.00

AC:

AN:

57562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000132

AC:

AN:

151332

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73862

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41214

American (AMR)

AF:

0.00

AC:

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67906

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Benign

0.51

DEOGEN2

Uncertain

0.60

Eigen

Benign

0.051

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.053

MetaRNN

Benign

0.29

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

1.3

PhyloP100

3.9

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.44

Sift

Benign

0.78

Sift4G

Benign

0.66

Polyphen

0.0040

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

Mutation Taster

=84/16

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over