chr22-45700294-G-A

Variant names:

• chr22-45700294-G-A
• rs199766375
• NM_013236.4:c.404G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_013236.4(ATXN10):​c.404G>A​(p.Gly135Asp) 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATXN10 NM_013236.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.43

Genes affected

ATXN10 (HGNC:10549): (ataxin 10) This gene encodes a protein that may function in neuron survival, neuron differentiation, and neuritogenesis. These roles may be carried out via activation of the mitogen-activated protein kinase cascade. Expansion of an ATTCT repeat from 9-32 copies to 800-4500 copies in an intronic region of this locus has been associated with spinocerebellar ataxia, type 10. Alternatively spliced transcript variants have been described.[provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN10	NM_013236.4	c.404G>A	p.Gly135Asp	missense_variant	Exon 4 of 12	ENST00000252934.10	NP_037368.1
ATXN10	NM_001167621.2	c.212G>A	p.Gly71Asp	missense_variant	Exon 3 of 11		NP_001161093.1
ATXN10	XM_047441314.1	c.404G>A	p.Gly135Asp	missense_variant	Exon 4 of 12		XP_047297270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATXN10	ENST00000252934.10	c.404G>A	p.Gly135Asp	missense_variant	Exon 4 of 12	1	NM_013236.4	ENSP00000252934.4
ATXN10	ENST00000381061.8	c.212G>A	p.Gly71Asp	missense_variant	Exon 3 of 11	2		ENSP00000370449.4
ATXN10	ENST00000470722.1	n.363G>A		non_coding_transcript_exon_variant	Exon 4 of 4	3
ATXN10	ENST00000498009.5	n.578G>A		non_coding_transcript_exon_variant	Exon 4 of 6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;D;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.9	.;L;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.1	D;D;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0070	D;D;.
Sift4G	Uncertain	0.010	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.90
MutPred		0.68		.;Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP		0.75
MPC		0.27
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.73
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs199766375; hg19: chr22-46096174;