NM_001195248.2:c.971A>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001195248.2(APTX):​c.971A>T​(p.Gln324Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00199 in 1,614,116 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0021 ( 4 hom. )

Consequence

APTX
NM_001195248.2 missense

Scores

1
4
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:8

Conservation

PhyloP100: 6.73
Variant links:
Genes affected
APTX (HGNC:15984): (aprataxin) This gene encodes a member of the histidine triad (HIT) superfamily. The encoded protein may play a role in single-stranded DNA repair through its nucleotide-binding activity and its diadenosine polyphosphate hydrolase activity. Mutations in this gene have been associated with ataxia-ocular apraxia. Alternatively spliced transcript variants have been identified for this gene.[provided by RefSeq, Aug 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.013023466).
BP6
Variant 9-32973556-T-A is Benign according to our data. Variant chr9-32973556-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136416.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=1, Likely_benign=3}. Variant chr9-32973556-T-A is described in Lovd as [Likely_benign]. Variant chr9-32973556-T-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00118 (179/152238) while in subpopulation NFE AF= 0.00221 (150/67996). AF 95% confidence interval is 0.00192. There are 1 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APTXNM_001195248.2 linkc.971A>T p.Gln324Leu missense_variant Exon 8 of 8 ENST00000379817.7 NP_001182177.2 Q7Z2E3-7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APTXENST00000379817.7 linkc.971A>T p.Gln324Leu missense_variant Exon 8 of 8 1 NM_001195248.2 ENSP00000369145.2 Q7Z2E3-7

Frequencies

GnomAD3 genomes
AF:
0.00118
AC:
179
AN:
152120
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000410
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000283
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00221
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.00113
AC:
283
AN:
251214
Hom.:
0
AF XY:
0.00118
AC XY:
160
AN XY:
135752
show subpopulations
Gnomad AFR exome
AF:
0.000492
Gnomad AMR exome
AF:
0.000376
Gnomad ASJ exome
AF:
0.0000993
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000693
Gnomad NFE exome
AF:
0.00217
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00207
AC:
3031
AN:
1461878
Hom.:
4
Cov.:
32
AF XY:
0.00197
AC XY:
1433
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.000388
Gnomad4 AMR exome
AF:
0.000313
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000337
Gnomad4 NFE exome
AF:
0.00263
Gnomad4 OTH exome
AF:
0.000944
GnomAD4 genome
AF:
0.00118
AC:
179
AN:
152238
Hom.:
1
Cov.:
32
AF XY:
0.00101
AC XY:
75
AN XY:
74432
show subpopulations
Gnomad4 AFR
AF:
0.000409
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000283
Gnomad4 NFE
AF:
0.00221
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00148
Hom.:
0
Bravo
AF:
0.00110
TwinsUK
AF:
0.00297
AC:
11
ALSPAC
AF:
0.00311
AC:
12
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00233
AC:
20
ExAC
AF:
0.00102
AC:
124
EpiCase
AF:
0.00256
EpiControl
AF:
0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:8
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:2
Dec 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 01, 2018
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 16, 2021
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:4
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 17, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: APTX c.971A>T (p.Gln324Leu) results in a non-conservative amino acid change located in the Zinc finger C2H2-type domain (IPR013087) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 1614116 control chromosomes, predominantly at a frequency of 0.0026 within the Non-Finnish European subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in APTX causing Ataxia, Early-Onset, With Oculomotor Apraxia And Hypoalbuminemia phenotype. To our knowledge, no occurrence of c.971A>T in individuals affected with Ataxia, Early-Onset, With Oculomotor Apraxia And Hypoalbuminemia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 136416). Based on the evidence outlined above, the variant was classified as likely benign. -

Apr 30, 2024
Athena Diagnostics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 09, 2014
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia Uncertain:2Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 29, 2023
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Coenzyme Q10 deficiency, Oculomotor Apraxia Type Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

APTX-related disorder Benign:1
Sep 17, 2020
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Uncertain
-0.070
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.23
.;.;.;.;T;.;.;.;.
Eigen
Benign
-0.19
Eigen_PC
Benign
-0.0021
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.59
T;T;T;.;T;.;.;T;T
M_CAP
Uncertain
0.093
D
MetaRNN
Benign
0.013
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Benign
1.7
.;.;.;.;L;.;.;.;.
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-2.1
.;.;N;N;N;N;N;N;.
REVEL
Benign
0.25
Sift
Benign
0.28
.;.;T;D;T;D;D;T;.
Sift4G
Benign
0.72
T;T;T;T;T;T;T;T;T
Polyphen
0.022, 0.0090, 0.0060
.;B;B;.;B;.;.;.;.
Vest4
0.36
MVP
0.99
MPC
0.077
ClinPred
0.024
T
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.38
gMVP
0.56

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.

Other links and lift over

dbSNP: rs141493373; hg19: chr9-32973554; API