3-53876009-C-G

Variant names:

• chr3-53876009-C-G
• rs752599288
• NM_022899.5:c.850G>C

Variant summary

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

The NM_022899.5(ACTR8):​c.850G>C​(p.Val284Leu) variant causes a missense change. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V284I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTR8 NM_022899.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.00
• Publications: 0 publications found

Genes affected

ACTR8 (HGNC:14672): (actin related protein 8) Predicted to enable ATP binding activity. Predicted to be involved in chromatin remodeling; double-strand break repair; and regulation of transcription, DNA-templated. Located in centrosome and nucleoplasm. Part of Ino80 complex. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.853

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022899.5. 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
	ACTR8	NM_022899.5	MANE Select	c.850G>C	p.Val284Leu	missense	Exon 7 of 13	NP_075050.3
	ACTR8	NM_001410774.1		c.517G>C	p.Val173Leu	missense	Exon 7 of 13	NP_001397703.1	Q9H981-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTR8	ENST00000335754.8	TSL:2 MANE Select	c.850G>C	p.Val284Leu	missense	Exon 7 of 13	ENSP00000336842.3	Q9H981-1
	ACTR8	ENST00000888053.1		c.850G>C	p.Val284Leu	missense	Exon 7 of 13	ENSP00000558112.1
	ACTR8	ENST00000963856.1		c.850G>C	p.Val284Leu	missense	Exon 7 of 14	ENSP00000633915.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.72
Sift	Benign	0.048	D
Sift4G	Benign	0.067	T
Polyphen		0.65	P
Vest4		0.84
MutPred		0.49		Loss of ubiquitination at K288 (P = 0.1278)
MVP		0.96
MPC		0.57
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.50
gMVP		0.71
Mutation Taster		=35/65	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: rs752599288; hg19: chr3-53910036;