X-13319407-T-A

Position:

• chrX-13319407-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001135995.2(ATXN3L):​c.528A>T​(p.Gln176His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ATXN3L NM_001135995.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.798

Genes affected

ATXN3L (HGNC:24173): (ataxin 3 like) This intronless gene may be a pseudogene (PMID:11450850). This gene is similar to the multi-exon gene which encodes ataxin 3 and contains a coding region which could encode a protein similar to ataxin 3. Mutations in the gene encoding ataxin 3 are associated with Machado-Joseph disease. [provided by RefSeq, Sep 2011]

GS1-600G8.3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.269076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN3L	NM_001135995.2	c.528A>T	p.Gln176His	missense_variant	1/1	ENST00000380622.5	NP_001129467.1
ATXN3L	NM_001387036.1	c.264A>T	p.Gln88His	missense_variant	2/2		NP_001373965.1
GS1-600G8.3	NR_046087.1	n.1848T>A		non_coding_transcript_exon_variant	16/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN3L	ENST00000380622.5	c.528A>T	p.Gln176His	missense_variant	1/1	6	NM_001135995.2	ENSP00000369996.2
GS1-600G8.3	ENST00000431486.1	n.1848T>A		non_coding_transcript_exon_variant	16/17	1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

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

Apr 07, 2022

The c.528A>T (p.Q176H) alteration is located in exon 1 (coding exon 1) of the ATXN3L gene. This alteration results from a A to T substitution at nucleotide position 528, causing the glutamine (Q) at amino acid position 176 to be replaced by a histidine (H). 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	0.32
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T;.
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Benign	0.087
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.65	P;.
Vest4		0.19
MutPred		0.38		Loss of solvent accessibility (P = 0.1651);.;
MVP		0.36
MPC		0.095
ClinPred		0.87	D
GERP RS		0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.66
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-13337526;