9-32986032-TAAAAAAAAA-TAAAAAAAAAA

Variant names:

• chr9-32986032-T-TA
• rs373304582
• NM_001195248.2:c.484-3dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001195248.2(APTX):​c.484-3dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: APTX NM_001195248.2 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.384
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 9-32986032-T-TA is Benign according to our data. Variant chr9-32986032-T-TA is described in ClinVar as Benign. ClinVar VariationId is 2767545.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 = 0.0203 (289/14240) while in subpopulation AFR AF = 0.0532 (270/5078). AF 95% confidence interval is 0.048. There are 0 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.484-3dupT		splice_region intron	N/A	NP_001182177.2
	APTX	NM_001195249.2		c.484-3dupT		splice_region intron	N/A	NP_001182178.1
	APTX	NM_001368995.1		c.484-3dupT		splice_region intron	N/A	NP_001355924.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APTX	ENST00000379817.7	TSL:1 MANE Select	c.484-3dupT		splice_region intron	N/A	ENSP00000369145.2
	APTX	ENST00000379819.6	TSL:1	c.484-3dupT		splice_region intron	N/A	ENSP00000369147.2
	APTX	ENST00000463596.6	TSL:1	c.484-3dupT		splice_region intron	N/A	ENSP00000419846.1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 288 AN: 14246 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00847

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: 0.00132

Gnomad OTH AF: 0.00862

GnomAD4 exome AF: 0.00145 AC: 1038 AN: 717576 Hom.: 3 Cov.: 10 AF XY: 0.00152 AC XY: 563 AN XY: 370954

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

African (AFR) AF: 0.0144 AC: 220 AN: 15270

American (AMR) AF: 0.00218 AC: 54 AN: 24734

Ashkenazi Jewish (ASJ) AF: 0.00106 AC: 17 AN: 16100

East Asian (EAS) AF: 0.00172 AC: 42 AN: 24440

South Asian (SAS) AF: 0.00354 AC: 182 AN: 51414

European-Finnish (FIN) AF: 0.000528 AC: 15 AN: 28412

Middle Eastern (MID) AF: 0.00131 AC: 3 AN: 2298

European-Non Finnish (NFE) AF: 0.000854 AC: 447 AN: 523184

Other (OTH) AF: 0.00183 AC: 58 AN: 31724

⚠️ 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: 0.0203 AC: 289 AN: 14240 Hom.: 0 Cov.: 0 AF XY: 0.0203 AC XY: 134 AN XY: 6598

African (AFR) AF: 0.0532 AC: 270 AN: 5078

American (AMR) AF: 0.00853 AC: 10 AN: 1172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 320

East Asian (EAS) AF: 0.00 AC: 0 AN: 462

South Asian (SAS) AF: 0.00 AC: 0 AN: 386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 44

European-Non Finnish (NFE) AF: 0.00132 AC: 8 AN: 6048

Other (OTH) AF: 0.00847 AC: 1 AN: 118

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38
Mutation Taster		=95/5	polymorphism

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: rs373304582; hg19: chr9-32986030;