X-13318988-G-A

Position:

chrX-13318988-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001135995.2(ATXN3L):c.947C>T(p.Thr316Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000993 in 1,208,781 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 38 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000098 ( 0 hom. 36 hem. )

Consequence

ATXN3L
NM_001135995.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.164

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 Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06931257).

BP6

Variant X-13318988-G-A is Benign according to our data. Variant chrX-13318988-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2660022.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN3L	NM_001135995.2 linkuse as main transcript	c.947C>T	p.Thr316Ile	missense_variant	1/1	ENST00000380622.5	NP_001129467.1	Q9H3M9B4DYC7
ATXN3L	NM_001387036.1 linkuse as main transcript	c.683C>T	p.Thr228Ile	missense_variant	2/2		NP_001373965.1
GS1-600G8.3	NR_046087.1 linkuse as main transcript	n.1449-20G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATXN3L	ENST00000380622.5 linkuse as main transcript	c.947C>T	p.Thr316Ile	missense_variant	1/1	6	NM_001135995.2	ENSP00000369996.2		Q9H3M9
GS1-600G8.3	ENST00000431486.1 linkuse as main transcript	n.1449-20G>A		intron_variant		1

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

112086

Hom.:

Cov.:

AF XY:

0.0000583

AC XY:

AN XY:

34322

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000226

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000884

AC:

AN:

181074

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

67482

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000629

Gnomad NFE exome

AF:

0.000173

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.0000985

AC:

108

AN:

1096695

Hom.:

Cov.:

AF XY:

0.0000991

AC XY:

AN XY:

363115

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.000125

Gnomad4 OTH exome

AF:

0.0000652

GnomAD4 genome

AF:

0.000107

AC:

AN:

112086

Hom.:

Cov.:

AF XY:

0.0000583

AC XY:

AN XY:

34322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000226

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ExAC

AF:

0.0000166

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

The c.947C>T (p.T316I) 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 947, causing the threonine (T) at amino acid position 316 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

ATXN3L: BP4, BS2; GS1-600G8.3: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.71

CADD

Benign

4.4

DANN

Benign

0.87

DEOGEN2

Benign

0.025

FATHMM_MKL

Benign

0.0051

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.013

MetaRNN

Benign

0.069

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.8

REVEL

Benign

0.035

Sift

Benign

0.036

Sift4G

Benign

0.18

Polyphen

0.11

Vest4

0.053

MutPred

0.17

Loss of phosphorylation at T316 (P = 0.0219);

MVP

0.66

MPC

0.38

ClinPred

0.052

GERP RS

0.79

Varity_R

0.13

gMVP

0.036

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