9-32973205-G-C

Variant names:

• chr9-32973205-G-C
• rs532688347
• NM_001195248.2:c.*293C>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001195248.2(APTX):​c.*293C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 531,222 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (5 hom.)
• Consequence: APTX NM_001195248.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.191

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-32973205-G-C is Benign according to our data. Variant chr9-32973205-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 913884.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000821 (125/152316) while in subpopulation SAS AF= 0.00414 (20/4826). AF 95% confidence interval is 0.00275. There are 0 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APTX	NM_001195248.2	c.*293C>G		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.*293C>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_001195248.2	ENSP00000369145.2

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00186 AC: 244 AN: 130852 Hom.: 1 AF XY: 0.00218 AC XY: 155 AN XY: 71248

Gnomad AFR exome AF: 0.000163

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.000246

Gnomad EAS exome AF: 0.0000953

Gnomad SAS exome AF: 0.00541

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00168

Gnomad OTH exome AF: 0.000999

GnomAD4 exome AF: 0.00181 AC: 685 AN: 378906 Hom.: 5 Cov.: 0 AF XY: 0.00214 AC XY: 450 AN XY: 210450

Gnomad4 AFR exome AF: 0.000172

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.000493

Gnomad4 EAS exome AF: 0.0000622

Gnomad4 SAS exome AF: 0.00544

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00135

Gnomad4 OTH exome AF: 0.00117

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74478

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.000797

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.71

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: rs532688347; hg19: chr9-32973203;