rs571475924

chr9-32984639-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001195248.2(APTX):c.762G>A(p.Pro254=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 1,614,184 control chromosomes in the GnomAD database, including 8 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 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (8 hom.)
• Consequence: APTX NM_001195248.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.690

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 9-32984639-C-T is Benign according to our data. Variant chr9-32984639-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281340.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000295 (45/152314) while in subpopulation SAS AF= 0.00622 (30/4822). AF 95% confidence interval is 0.00448. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APTX	NM_001195248.2	c.762G>A	p.Pro254=	synonymous_variant	6/8	ENST00000379817.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APTX	ENST00000379817.7	c.762G>A	p.Pro254=	synonymous_variant	6/8	1	NM_001195248.2	P1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000840 AC: 211 AN: 251104 Hom.: 3 AF XY: 0.00105 AC XY: 142 AN XY: 135752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00581

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000506 AC: 739 AN: 1461870 Hom.: 8 Cov.: 32 AF XY: 0.000685 AC XY: 498 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00655

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.0000782

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74472

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.000140

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2020	- -

Coenzyme Q10 deficiency, Oculomotor Apraxia Type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 11, 2015

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.29
Cadd	Benign	9.9
Dann	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs571475924; hg19: chr9-32984637; COSMIC: COSV58929185; COSMIC: COSV58929185;