3-53874273-T-C

Position:

• chr3-53874273-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022899.5(ACTR8):​c.1003A>G​(p.Thr335Ala) variant causes a missense 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTR8 NM_022899.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.111

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10430688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTR8	NM_022899.5	c.1003A>G	p.Thr335Ala	missense_variant	8/13	ENST00000335754.8	NP_075050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTR8	ENST00000335754.8	c.1003A>G	p.Thr335Ala	missense_variant	8/13	2	NM_022899.5	ENSP00000336842	P1
ACTR8	ENST00000482349.5	c.670A>G	p.Thr224Ala	missense_variant	8/13	2		ENSP00000419429
ACTR8	ENST00000486794.1	c.308-1127A>G		intron_variant		2		ENSP00000417230

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Feb 07, 2023

The c.1003A>G (p.T335A) alteration is located in exon 8 (coding exon 8) of the ACTR8 gene. This alteration results from a A to G substitution at nucleotide position 1003, causing the threonine (T) at amino acid position 335 to be replaced by an alanine (A). 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	Benign	0.061
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.66
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.39	N;N
REVEL	Benign	0.21
Sift	Benign	0.74	T;T
Sift4G	Benign	0.84	T;T
Polyphen		0.0	B;.
Vest4		0.26
MutPred		0.53		Gain of ubiquitination at K337 (P = 0.1103);.;
MVP		0.79
MPC		0.24
ClinPred		0.027	T
GERP RS		0.62
Varity_R		0.048
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-53908300;