Genetic Variant ATXN10:p.Asp113Gly (chr22-45693025-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_013236.4(ATXN10):c.338A>G(p.Asp113Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ATXN10
NM_013236.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.92

Variant links:

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]

ATXN10 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18227562).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATXN10	NM_013236.4 link	c.338A>G	p.Asp113Gly	missense_variant	Exon 3 of 12	ENST00000252934.10	NP_037368.1	Q9UBB4-1
ATXN10	NM_001167621.2 link	c.146A>G	p.Asp49Gly	missense_variant	Exon 2 of 11		NP_001161093.1	Q9UBB4-2
ATXN10	XM_047441314.1 link	c.338A>G	p.Asp113Gly	missense_variant	Exon 3 of 12		XP_047297270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATXN10	ENST00000252934.10 link	c.338A>G	p.Asp113Gly	missense_variant	Exon 3 of 12	1	NM_013236.4	ENSP00000252934.4	Q9UBB4-1
ATXN10	ENST00000381061.8 link	c.146A>G	p.Asp49Gly	missense_variant	Exon 2 of 11	2		ENSP00000370449.4	Q9UBB4-2
ATXN10	ENST00000470722.1 link	n.297A>G		non_coding_transcript_exon_variant	Exon 3 of 4	3
ATXN10	ENST00000498009.5 link	n.512A>G		non_coding_transcript_exon_variant	Exon 3 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00110

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251442

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135898

show subpopulations

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:

0.0000264

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727196

show subpopulations

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:

0.0000216

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000538

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Oct 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.338A>G (p.D113G) alteration is located in exon 3 (coding exon 3) of the ATXN10 gene. This alteration results from a A to G substitution at nucleotide position 338, causing the aspartic acid (D) at amino acid position 113 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

Benign

0.28

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

.;T;.

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.82

T;T;T

M_CAP

Benign

0.0088

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.90

.;L;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.5

N;N;.

REVEL

Benign

0.092

Sift

Benign

0.12

T;T;.

Sift4G

Benign

0.45

T;T;.

Polyphen

0.85

.;P;.

Vest4

0.63

MVP

0.56

MPC

0.096

ClinPred

0.39

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.29

gMVP

0.34

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