9-32986032-TAAAAAAAAA-TAAAAAAA

Variant names:

• chr9-32986032-TAA-T
• rs373304582
• NM_001195248.2:c.484-4_484-3delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001195248.2(APTX):​c.484-4_484-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000362 in 718,810 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: APTX NM_001195248.2 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.608
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 9-32986032-TAA-T is Benign according to our data. Variant chr9-32986032-TAA-T is described in ClinVar as Benign. ClinVar VariationId is 2720059.Status of the report is criteria_provided_single_submitter, 1 stars.

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.484-4_484-3delTT		splice_region intron	N/A	NP_001182177.2
	APTX	NM_001195249.2		c.484-4_484-3delTT		splice_region intron	N/A	NP_001182178.1
	APTX	NM_001368995.1		c.484-4_484-3delTT		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.484-4_484-3delTT		splice_region intron	N/A	ENSP00000369145.2
	APTX	ENST00000379819.6	TSL:1	c.484-4_484-3delTT		splice_region intron	N/A	ENSP00000369147.2
	APTX	ENST00000463596.6	TSL:1	c.484-4_484-3delTT		splice_region intron	N/A	ENSP00000419846.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000362 AC: 26 AN: 718810 Hom.: 0 AF XY: 0.0000377 AC XY: 14 AN XY: 371582

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

African (AFR) AF: 0.00 AC: 0 AN: 15458

American (AMR) AF: 0.0000403 AC: 1 AN: 24804

Ashkenazi Jewish (ASJ) AF: 0.000124 AC: 2 AN: 16118

East Asian (EAS) AF: 0.0000818 AC: 2 AN: 24458

South Asian (SAS) AF: 0.000136 AC: 7 AN: 51528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2306

European-Non Finnish (NFE) AF: 0.0000267 AC: 14 AN: 523894

Other (OTH) AF: 0.00 AC: 0 AN: 31800

⚠️ 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 Cov.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.61
Mutation Taster		=88/12	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;