9-32974572-GAAA-GAAAAA

Variant names:

• chr9-32974572-G-GAA
• rs34600530
• NM_001195248.2:c.771-13_771-12dupTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP6_Very_Strong BS1

The NM_001195248.2(APTX):​c.771-13_771-12dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00683 in 1,326,036 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0077 (1 hom.)
• Consequence: APTX NM_001195248.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0780
• Publications: 4 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM2: Variant has high frequency in the EAS (0.0132) population. However there is too low homozygotes in high coverage region: (expected more than 15, got 1).
• BP6: Variant 9-32974572-G-GAA is Benign according to our data. Variant chr9-32974572-G-GAA is described in ClinVar as Benign. ClinVar VariationId is 235248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000397 (60/151200) while in subpopulation EAS AF = 0.00934 (48/5138). AF 95% confidence interval is 0.00724. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APTX	NM_001195248.2	MANE Select	c.771-13_771-12dupTT		intron	N/A	NP_001182177.2
	APTX	NM_001195249.2		c.771-13_771-12dupTT		intron	N/A	NP_001182178.1
	APTX	NM_001368995.1		c.771-13_771-12dupTT		intron	N/A	NP_001355924.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APTX	ENST00000379817.7	TSL:1 MANE Select	c.771-13_771-12dupTT		intron	N/A	ENSP00000369145.2
	APTX	ENST00000379819.6	TSL:1	c.771-13_771-12dupTT		intron	N/A	ENSP00000369147.2
	APTX	ENST00000463596.6	TSL:1	c.771-13_771-12dupTT		intron	N/A	ENSP00000419846.1

Frequencies

GnomAD3 genomes AF: 0.000397 AC: 60 AN: 151088 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00932

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.0000968

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.00270 AC: 582 AN: 215722 AF XY: 0.00256

Gnomad AFR exome AF: 0.000878

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.000551

Gnomad EAS exome AF: 0.0121

Gnomad FIN exome AF: 0.00442

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00224

GnomAD4 exome AF: 0.00766 AC: 8996 AN: 1174836 Hom.: 1 Cov.: 22 AF XY: 0.00717 AC XY: 4249 AN XY: 592628

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00441 AC: 125 AN: 28360

American (AMR) AF: 0.00318 AC: 128 AN: 40254

Ashkenazi Jewish (ASJ) AF: 0.00340 AC: 79 AN: 23232

East Asian (EAS) AF: 0.0143 AC: 468 AN: 32786

South Asian (SAS) AF: 0.00565 AC: 406 AN: 71838

European-Finnish (FIN) AF: 0.00531 AC: 226 AN: 42568

Middle Eastern (MID) AF: 0.00311 AC: 15 AN: 4818

European-Non Finnish (NFE) AF: 0.00813 AC: 7161 AN: 881082

Other (OTH) AF: 0.00778 AC: 388 AN: 49898

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000397 AC: 60 AN: 151200 Hom.: 0 Cov.: 0 AF XY: 0.000488 AC XY: 36 AN XY: 73812

African (AFR) AF: 0.00 AC: 0 AN: 41214

American (AMR) AF: 0.000132 AC: 2 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00934 AC: 48 AN: 5138

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4788

European-Finnish (FIN) AF: 0.0000968 AC: 1 AN: 10332

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67768

Other (OTH) AF: 0.000477 AC: 1 AN: 2098

Alfa AF: 0.0189 Hom.: 2452

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.078
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34600530; hg19: chr9-32974570;