3-53871420-G-A

Variant summary

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

The NM_022899.5(ACTR8):c.1379C>T(p.Ser460Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ACTR8 NM_022899.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.88

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTR8	NM_022899.5	c.1379C>T	p.Ser460Phe	missense_variant	11/13	ENST00000335754.8
ACTR8	NM_001410774.1	c.1046C>T	p.Ser349Phe	missense_variant	11/13
ACTR8	XM_005265587.6	c.1379C>T	p.Ser460Phe	missense_variant	11/14
ACTR8	XM_047449238.1	c.653C>T	p.Ser218Phe	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTR8	ENST00000335754.8	c.1379C>T	p.Ser460Phe	missense_variant	11/13	2	NM_022899.5	P1
ACTR8	ENST00000482349.5	c.1046C>T	p.Ser349Phe	missense_variant	11/13	2
ACTR8	ENST00000486794.1	c.641C>T	p.Ser214Phe	missense_variant	6/8	2
ACTR8	ENST00000495993.1	n.255C>T		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461858 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

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

Jan 10, 2023

The c.1379C>T (p.S460F) alteration is located in exon 11 (coding exon 11) of the ACTR8 gene. This alteration results from a C to T substitution at nucleotide position 1379, causing the serine (S) at amino acid position 460 to be replaced by a phenylalanine (F). 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	0.12
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.037	T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.060	T;T
Polyphen		0.79	P;.
Vest4		0.52
MutPred		0.33		Loss of phosphorylation at S460 (P = 0.0194);.;
MVP		0.97
MPC		0.72
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.13
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1030608705; hg19: chr3-53905447; COSMIC: COSV99213887; COSMIC: COSV99213887;