9-32986032-TAAAAAAAAA-TAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001195248.2(APTX):​c.484-3delT 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (3 hom., cov: 0)
  • Exomes 𝑓: 0.12 (3871 hom.)
• Consequence: APTX NM_001195248.2 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 9-32986032-TA-T is Benign according to our data. Variant chr9-32986032-TA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

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.484-3delT		splice_region intron	N/A	NP_001182177.2	Q7Z2E3-7
	APTX	NM_001195249.2		c.484-3delT		splice_region intron	N/A	NP_001182178.1	Q7Z2E3-7
	APTX	NM_001368995.1		c.484-3delT		splice_region intron	N/A	NP_001355924.1	Q7Z2E3-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APTX	ENST00000379817.7	TSL:1 MANE Select	c.484-3delT		splice_region intron	N/A	ENSP00000369145.2	Q7Z2E3-7
	APTX	ENST00000379819.6	TSL:1	c.484-3delT		splice_region intron	N/A	ENSP00000369147.2	Q7Z2E3-7
	APTX	ENST00000463596.6	TSL:1	c.484-3delT		splice_region intron	N/A	ENSP00000419846.1	Q7Z2E3-7

Frequencies

GnomAD3 genomes AF: 0.0543 AC: 775 AN: 14270 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.0179

Gnomad AMR AF: 0.0559

Gnomad ASJ AF: 0.0350

Gnomad EAS AF: 0.0773

Gnomad SAS AF: 0.0825

Gnomad FIN AF: 0.0529

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.0447

Gnomad OTH AF: 0.0431

GnomAD4 exome AF: 0.116 AC: 78355 AN: 675950 Hom.: 3871 Cov.: 10 AF XY: 0.117 AC XY: 40858 AN XY: 348316

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

African (AFR) AF: 0.0991 AC: 1460 AN: 14730

American (AMR) AF: 0.112 AC: 2574 AN: 23024

Ashkenazi Jewish (ASJ) AF: 0.0987 AC: 1498 AN: 15180

East Asian (EAS) AF: 0.208 AC: 4530 AN: 21772

South Asian (SAS) AF: 0.134 AC: 6129 AN: 45874

European-Finnish (FIN) AF: 0.137 AC: 3576 AN: 26196

Middle Eastern (MID) AF: 0.110 AC: 238 AN: 2156

European-Non Finnish (NFE) AF: 0.110 AC: 54795 AN: 497334

Other (OTH) AF: 0.120 AC: 3555 AN: 29684

⚠️ 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: 0.0544 AC: 776 AN: 14268 Hom.: 3 Cov.: 0 AF XY: 0.0549 AC XY: 362 AN XY: 6598

African (AFR) AF: 0.0613 AC: 315 AN: 5136

American (AMR) AF: 0.0563 AC: 66 AN: 1172

Ashkenazi Jewish (ASJ) AF: 0.0350 AC: 11 AN: 314

East Asian (EAS) AF: 0.0779 AC: 36 AN: 462

South Asian (SAS) AF: 0.0829 AC: 32 AN: 386

European-Finnish (FIN) AF: 0.0529 AC: 29 AN: 548

Middle Eastern (MID) AF: 0.250 AC: 11 AN: 44

European-Non Finnish (NFE) AF: 0.0448 AC: 270 AN: 6032

Other (OTH) AF: 0.0424 AC: 5 AN: 118

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38
Mutation Taster		=97/3	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs373304582; hg19: chr9-32986030; COSMIC: COSV58928012; COSMIC: COSV58928012;