X-13319531-G-A

Position:

• chrX-13319531-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001135995.2(ATXN3L):​c.404C>T​(p.Ser135Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,964 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: ATXN3L NM_001135995.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN3L	NM_001135995.2	c.404C>T	p.Ser135Phe	missense_variant	1/1	ENST00000380622.5	NP_001129467.1
ATXN3L	NM_001387036.1	c.235-95C>T		intron_variant			NP_001373965.1
GS1-600G8.3	NR_046087.1	n.1934+38G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN3L	ENST00000380622.5	c.404C>T	p.Ser135Phe	missense_variant	1/1	6	NM_001135995.2	ENSP00000369996.2
GS1-600G8.3	ENST00000431486.1	n.1934+38G>A		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097964 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363324

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jan 24, 2024

The c.404C>T (p.S135F) alteration is located in exon 1 (coding exon 1) of the ATXN3L gene. This alteration results from a C to T substitution at nucleotide position 404, causing the serine (S) at amino acid position 135 to be replaced by a phenylalanine (F). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.9	D;.
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.020	D;D
Polyphen		1.0	D;.
Vest4		0.57
MutPred		0.95		Loss of sheet (P = 0.1398);.;
MVP		0.61
MPC		0.45
ClinPred		1.0	D
GERP RS		0.66
Varity_R		0.87
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1391192608; hg19: chrX-13337650; COSMIC: COSV66075518;