3-53877377-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022899.5(ACTR8):c.521T>G(p.Val174Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTR8 NM_022899.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.91

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTR8	NM_022899.5	c.521T>G	p.Val174Gly	missense_variant	5/13	ENST00000335754.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTR8	ENST00000335754.8	c.521T>G	p.Val174Gly	missense_variant	5/13	2	NM_022899.5	P1
ACTR8	ENST00000482349.5	c.188T>G	p.Val63Gly	missense_variant	5/13	2
ACTR8	ENST00000498740.1	c.188T>G	p.Val63Gly	missense_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000415 AC: 1 AN: 240728 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129964

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000904

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 2022

The c.521T>G (p.V174G) alteration is located in exon 5 (coding exon 5) of the ACTR8 gene. This alteration results from a T to G substitution at nucleotide position 521, causing the valine (V) at amino acid position 174 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.77	P;.;.
Vest4		0.61
MutPred		0.74		Loss of stability (P = 0.0154);.;.;
MVP		0.98
MPC		1.0
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.92
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1273252274; hg19: chr3-53911404;