rs104894103

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_001195248.2(APTX):ā€‹c.837G>Cā€‹(p.Trp279Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W279R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

APTX
NM_001195248.2 missense

Scores

15
2
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.40
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 Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a domain HIT (size 105) in uniprot entity APTX_HUMAN there are 24 pathogenic changes around while only 2 benign (92%) in NM_001195248.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-32974497-A-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
APTXNM_001195248.2 linkuse as main transcriptc.837G>C p.Trp279Cys missense_variant 7/8 ENST00000379817.7 NP_001182177.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
APTXENST00000379817.7 linkuse as main transcriptc.837G>C p.Trp279Cys missense_variant 7/81 NM_001195248.2 ENSP00000369145 P1Q7Z2E3-7

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250908
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135634
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:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1456924
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
725136
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:
9.03e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.89
.;.;.;.;.;D;.;.;.;.
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D;D;.;D;.;.;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.1
M;.;.;.;.;M;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-13
D;.;.;D;D;D;D;D;D;.
REVEL
Pathogenic
0.83
Sift
Pathogenic
0.0
D;.;.;D;D;D;D;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;D;D;.;D;.;.;.;.
Vest4
0.98
MutPred
0.65
Gain of sheet (P = 0.0477);.;.;.;.;Gain of sheet (P = 0.0477);.;.;.;.;
MVP
0.94
MPC
0.45
ClinPred
0.98
D
GERP RS
6.0
Varity_R
0.99
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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: rs104894103; hg19: chr9-32974493; API