22-45702735-A-T

Variant names:

• chr22-45702735-A-T
• rs758820148
• NM_013236.4:c.535A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_013236.4(ATXN10):​c.535A>T​(p.Met179Leu) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M179V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATXN10 NM_013236.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.19
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

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.535A>T	p.Met179Leu	missense	Exon 5 of 12	NP_037368.1	Q9UBB4-1
	ATXN10	NM_001167621.2		c.343A>T	p.Met115Leu	missense	Exon 4 of 11	NP_001161093.1	Q9UBB4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN10	ENST00000252934.10	TSL:1 MANE Select	c.535A>T	p.Met179Leu	missense	Exon 5 of 12	ENSP00000252934.4	Q9UBB4-1
	ATXN10	ENST00000381061.8	TSL:2	c.343A>T	p.Met115Leu	missense	Exon 4 of 11	ENSP00000370449.4	Q9UBB4-2
	ATXN10	ENST00000498009.5	TSL:5	n.709A>T		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		6.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.78		Loss of sheet (P = 0.0817)
MVP		0.66
MPC		0.24
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.72
gMVP		0.61
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs758820148; hg19: chr22-46098615;