Variant X-13319240-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001135995.2(ATXN3L):c.695C>T(p.Ala232Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000364 in 1,209,333 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000034 ( 0 hom. 9 hem. )

Consequence

ATXN3L
NM_001135995.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.14

Variant links:

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]

ATXN3L links:

GS1-600G8.3 (HGNC:):

GS1-600G8.3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07308301).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN3L	NM_001135995.2 linkuse as main transcript	c.695C>T	p.Ala232Val	missense_variant	1/1	ENST00000380622.5	NP_001129467.1	Q9H3M9B4DYC7
ATXN3L	NM_001387036.1 linkuse as main transcript	c.431C>T	p.Ala144Val	missense_variant	2/2		NP_001373965.1
GS1-600G8.3	NR_046087.1 linkuse as main transcript	n.1681G>A		non_coding_transcript_exon_variant	16/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN3L	ENST00000380622.5 linkuse as main transcript	c.695C>T	p.Ala232Val	missense_variant	1/1	6	NM_001135995.2	ENSP00000369996.2		Q9H3M9
GS1-600G8.3	ENST00000431486.1 linkuse as main transcript	n.1681G>A		non_coding_transcript_exon_variant	16/17	1

Frequencies

GnomAD3 genomes

AF:

0.0000626

AC:

AN:

111775

Hom.:

Cov.:

AF XY:

0.0000883

AC XY:

AN XY:

33963

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000571

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:

0.00

Gnomad OTH

AF:

0.000662

GnomAD3 exomes

AF:

0.000150

AC:

AN:

180116

Hom.:

AF XY:

0.0000900

AC XY:

AN XY:

66682

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000989

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000337

AC:

AN:

1097558

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

362994

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000995

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:

0.00

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000626

AC:

AN:

111775

Hom.:

Cov.:

AF XY:

0.0000883

AC XY:

AN XY:

33963

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000571

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000662

Bravo

AF:

0.000144

ExAC

AF:

0.000158

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2024

The c.695C>T (p.A232V) 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 695, causing the alanine (A) at amino acid position 232 to be replaced by a valine (V). 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

0.17

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.88

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.0075

MetaRNN

Benign

0.073

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.24

Sift

Benign

0.040

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.16

MutPred

0.37

Loss of helix (P = 0.2022);

MVP

0.32

MPC

0.27

ClinPred

0.30

GERP RS

-0.16

Varity_R

0.19

gMVP

0.39

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