Genetic Variant ATXN10:p.Arg5Trp (chr22-45672076-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_013236.4(ATXN10):c.13A>T(p.Arg5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

ATXN10
NM_013236.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.08

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

spinocerebellar ataxia type 10
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ATXN10 links:

ENSG00000280383 (HGNC:):

ENSG00000280383 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26646984).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013236.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN10	NM_013236.4	MANE Select	c.13A>T	p.Arg5Trp	missense	Exon 1 of 12	NP_037368.1	Q9UBB4-1
	ATXN10	NM_001167621.2		c.13A>T	p.Arg5Trp	missense	Exon 1 of 11	NP_001161093.1	Q9UBB4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATXN10	ENST00000252934.10	TSL:1 MANE Select	c.13A>T	p.Arg5Trp	missense	Exon 1 of 12	ENSP00000252934.4	Q9UBB4-1
ATXN10	ENST00000381061.8	TSL:2	c.13A>T	p.Arg5Trp	missense	Exon 1 of 11	ENSP00000370449.4	Q9UBB4-2
ENSG00000280383	ENST00000623075.1	TSL:6	n.15058A>T		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.22e-7

AC:

AN:

1385204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

683628

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31422

American (AMR)

AF:

0.00

AC:

AN:

35552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25048

East Asian (EAS)

AF:

0.00

AC:

AN:

35616

South Asian (SAS)

AF:

0.00

AC:

AN:

79064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077128

Other (OTH)

AF:

0.00

AC:

AN:

57746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

-0.092

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

PhyloP100

1.1

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.2

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.30

MutPred

0.28

Loss of disorder (P = 0.0111)

MVP

0.17

MPC

0.23

ClinPred

0.90

GERP RS

0.54

PromoterAI

-0.15

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.39

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over