rs150886026

Variant names:

• chr9-32984805-C-T
• rs150886026
• NM_001195248.2:c.596G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001195248.2(APTX):​c.596G>A​(p.Arg199His) variant causes a missense change. The variant allele was found at a frequency of 0.0011 in 1,614,150 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R199C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0055 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (9 hom.)
• Consequence: APTX NM_001195248.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.16
• Publications: 7 publications found

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]

APTX Gene-Disease associations (from GenCC):

• ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001195248.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.012209952).
• BP6: Variant 9-32984805-C-T is Benign according to our data. Variant chr9-32984805-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 214120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00547 (833/152274) while in subpopulation AFR AF = 0.0188 (780/41546). AF 95% confidence interval is 0.0177. There are 10 homozygotes in GnomAd4. There are 389 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195248.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APTX	NM_001195248.2	MANE Select	c.596G>A	p.Arg199His	missense	Exon 6 of 8	NP_001182177.2	Q7Z2E3-7
	APTX	NM_001195249.2		c.596G>A	p.Arg199His	missense	Exon 6 of 8	NP_001182178.1	Q7Z2E3-7
	APTX	NM_001368995.1		c.596G>A	p.Arg199His	missense	Exon 6 of 8	NP_001355924.1	Q7Z2E3-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APTX	ENST00000379817.7	TSL:1 MANE Select	c.596G>A	p.Arg199His	missense	Exon 6 of 8	ENSP00000369145.2	Q7Z2E3-7
	APTX	ENST00000379819.6	TSL:1	c.596G>A	p.Arg199His	missense	Exon 7 of 9	ENSP00000369147.2	Q7Z2E3-7
	APTX	ENST00000463596.6	TSL:1	c.596G>A	p.Arg199His	missense	Exon 6 of 8	ENSP00000419846.1	Q7Z2E3-7

Frequencies

GnomAD3 genomes AF: 0.00547 AC: 832 AN: 152156 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00163 AC: 410 AN: 251468 AF XY: 0.00136

Gnomad AFR exome AF: 0.0195

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000642 AC: 939 AN: 1461876 Hom.: 9 Cov.: 32 AF XY: 0.000626 AC XY: 455 AN XY: 727242

African (AFR) AF: 0.0196 AC: 656 AN: 33480

American (AMR) AF: 0.00127 AC: 57 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00118 AC: 102 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1112008

Other (OTH) AF: 0.00132 AC: 80 AN: 60394

GnomAD4 genome AF: 0.00547 AC: 833 AN: 152274 Hom.: 10 Cov.: 32 AF XY: 0.00522 AC XY: 389 AN XY: 74454

African (AFR) AF: 0.0188 AC: 780 AN: 41546

American (AMR) AF: 0.00242 AC: 37 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68018

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00219 Hom.: 7

Bravo AF: 0.00627

ESP6500AA AF: 0.0182 AC: 80

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00207 AC: 251

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	APTX-related disorder (1)
-	-	1	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.59
Sift	Benign	0.061	T
Sift4G	Benign	0.073	T
Polyphen		0.77	P
Vest4		0.86
MVP		0.97
MPC		0.28
ClinPred		0.021	T
GERP RS		4.0
Varity_R		0.40
gMVP		0.60
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs150886026; hg19: chr9-32984803;