NM_001195248.2:c.*141G>A

Variant names:

• chr9-32973357-C-T
• rs148292963
• NM_001195248.2:c.*141G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001195248.2(APTX):​c.*141G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 995,456 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (1 hom.)
• Consequence: APTX NM_001195248.2 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.315

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 9-32973357-C-T is Benign according to our data. Variant chr9-32973357-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 915132.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 = 0.00411 (626/152234) while in subpopulation AFR AF= 0.0144 (598/41534). AF 95% confidence interval is 0.0134. There are 6 homozygotes in gnomad4. There are 290 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APTX	NM_001195248.2	c.*141G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000379817.7	NP_001182177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APTX	ENST00000379817	c.*141G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_001195248.2	ENSP00000369145.2

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 625 AN: 152116 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

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: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000995 AC: 182 AN: 182884 Hom.: 0 AF XY: 0.000729 AC XY: 73 AN XY: 100126

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.000601

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000509

Gnomad OTH exome AF: 0.000400

GnomAD4 exome AF: 0.000458 AC: 386 AN: 843222 Hom.: 1 Cov.: 12 AF XY: 0.000381 AC XY: 168 AN XY: 440706

Gnomad4 AFR exome AF: 0.0140

Gnomad4 AMR exome AF: 0.000600

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000427

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000331

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00411 AC: 626 AN: 152234 Hom.: 6 Cov.: 32 AF XY: 0.00390 AC XY: 290 AN XY: 74428

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00231 Hom.: 0

Bravo AF: 0.00507

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 24, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.4
DANN	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs148292963; hg19: chr9-32973355;