3-179574447-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_004301.5(ACTL6A):​c.456C>T​(p.Cys152Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTL6A NM_004301.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Illumina, Orphanet
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

LOC124909462 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 3-179574447-C-T is Benign according to our data. Variant chr3-179574447-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3027056.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.563 with no splicing effect.

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>T	p.Cys152Cys	synonymous	Exon 5 of 14	NP_004292.1	O96019-1
	ACTL6A	NM_177989.4		c.330C>T	p.Cys110Cys	synonymous	Exon 5 of 14	NP_817126.1	O96019-2
	ACTL6A	NM_178042.4		c.330C>T	p.Cys110Cys	synonymous	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>T	p.Cys152Cys	synonymous	Exon 5 of 14	ENSP00000397552.2	O96019-1
	ACTL6A	ENST00000450518.6	TSL:1	c.330C>T	p.Cys110Cys	synonymous	Exon 5 of 14	ENSP00000394014.2	O96019-2
	ACTL6A	ENST00000879836.1		c.450C>T	p.Cys150Cys	synonymous	Exon 5 of 14	ENSP00000549895.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251246 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	11
DANN	Benign	0.54
PhyloP100		0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;