3-179569865-G-T

Variant names:

• chr3-179569865-G-T
• rs780327011
• ENST00000450518.6:c.-60G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_177989.4(ACTL6A):​c.-60G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTL6A NM_177989.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.01
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177989.4. 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.67G>T	p.Val23Leu	missense	Exon 2 of 14	NP_004292.1	O96019-1
	ACTL6A	NM_177989.4		c.-60G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	NP_817126.1	O96019-2
	ACTL6A	NM_178042.4		c.-60G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	NP_829888.1	O96019-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTL6A	ENST00000450518.6	TSL:1	c.-60G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	ENSP00000394014.2	O96019-2
	ACTL6A	ENST00000429709.7	TSL:1 MANE Select	c.67G>T	p.Val23Leu	missense	Exon 2 of 14	ENSP00000397552.2	O96019-1
	ACTL6A	ENST00000450518.6	TSL:1	c.-60G>T		5_prime_UTR	Exon 2 of 14	ENSP00000394014.2	O96019-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.023
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.073	D
MutationAssessor	Benign	1.1	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.12	N
REVEL	Uncertain	0.33
Sift	Benign	0.86	T
Sift4G	Benign	0.48	T
Polyphen		0.0040	B
Vest4		0.70
MutPred		0.54		Gain of glycosylation at Y27 (P = 0.0138)
MVP		0.84
MPC		0.88
ClinPred		0.89	D
GERP RS		4.3
Varity_R		0.23
gMVP		0.74
Mutation Taster		=204/96	polymorphism

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: rs780327011; hg19: chr3-179287653;