chr3-179574447-C-G

Variant names:

• chr3-179574447-C-G
• rs111350774
• NM_004301.5:c.456C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004301.5(ACTL6A):​c.456C>G​(p.Cys152Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C152C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTL6A NM_004301.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.563
• Publications: 0 publications found

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

LOC124909462 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTL6A	NM_004301.5	MANE Select	c.456C>G	p.Cys152Trp	missense	Exon 5 of 14	NP_004292.1	O96019-1
	ACTL6A	NM_177989.4		c.330C>G	p.Cys110Trp	missense	Exon 5 of 14	NP_817126.1	O96019-2
	ACTL6A	NM_178042.4		c.330C>G	p.Cys110Trp	missense	Exon 5 of 14	NP_829888.1	O96019-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTL6A	ENST00000429709.7	TSL:1 MANE Select	c.456C>G	p.Cys152Trp	missense	Exon 5 of 14	ENSP00000397552.2	O96019-1
	ACTL6A	ENST00000450518.6	TSL:1	c.330C>G	p.Cys110Trp	missense	Exon 5 of 14	ENSP00000394014.2	O96019-2
	ACTL6A	ENST00000879836.1		c.450C>G	p.Cys150Trp	missense	Exon 5 of 14	ENSP00000549895.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.56
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.75		Loss of methylation at K153 (P = 0.0172)
MVP		0.99
MPC		2.3
ClinPred		0.99	D
GERP RS		0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.98
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs111350774; hg19: chr3-179292235;