Variant 3-53868814-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_022899.5(ACTR8):c.1780T>G(p.Cys594Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

ACTR8
NM_022899.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.81

Variant links:

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]

ACTR8 links:

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ACMG classification

Classification made for transcript

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, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTR8	NM_022899.5 link	c.1780T>G	p.Cys594Gly	missense_variant	Exon 13 of 13	ENST00000335754.8	NP_075050.3	Q9H981-1
ACTR8	NM_001410774.1 link	c.1447T>G	p.Cys483Gly	missense_variant	Exon 13 of 13		NP_001397703.1
ACTR8	XM_005265587.6 link	c.1780T>G	p.Cys594Gly	missense_variant	Exon 13 of 14		XP_005265644.1	Q9H981-1
ACTR8	XM_047449238.1 link	c.1054T>G	p.Cys352Gly	missense_variant	Exon 8 of 8		XP_047305194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACTR8	ENST00000335754.8 link	c.1780T>G	p.Cys594Gly	missense_variant	Exon 13 of 13	2	NM_022899.5	ENSP00000336842.3	Q9H981-1
ACTR8	ENST00000482349.5 link	c.1447T>G	p.Cys483Gly	missense_variant	Exon 13 of 13	2		ENSP00000419429.1	Q9H981-2
ACTR8	ENST00000486794.1 link	c.1039T>G	p.Cys347Gly	missense_variant	Exon 8 of 8	2		ENSP00000417230.1	H0Y849
ACTR8	ENST00000488802.1 link	n.365T>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1780T>G (p.C594G) alteration is located in exon 13 (coding exon 13) of the ACTR8 gene. This alteration results from a T to G substitution at nucleotide position 1780, causing the cysteine (C) at amino acid position 594 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

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.61

D;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-7.6

D;D

REVEL

Pathogenic

0.88

Sift

Benign

0.093

T;D

Sift4G

Benign

0.11

T;T

Polyphen

0.85

P;.

Vest4

0.88

MutPred

0.60

Loss of stability (P = 0.0145);.;

MVP

0.99

MPC

0.97

ClinPred

0.99

GERP RS

5.9

Varity_R

0.87

gMVP

0.58

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over