rs200922655

Variant names:

• chr9-32986034-AAAAAAAAACAAAAAAAAAAAC-A
• rs200922655
• NM_001195248.2:c.484-25_484-5delGTTTTTTTTTTTGTTTTTTTT

Variant summary

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

The ENST00000379817.7(APTX):​c.484-25_484-5delGTTTTTTTTTTTGTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,277,180 control chromosomes in the GnomAD database, including 14,600 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (7125 hom., cov: 0)
  • Exomes 𝑓: 0.27 (7475 hom.)
• Consequence: APTX ENST00000379817.7 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.13
• 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 -16 ACMG points.

• BP6: Variant 9-32986034-AAAAAAAAACAAAAAAAAAAAC-A is Benign according to our data. Variant chr9-32986034-AAAAAAAAACAAAAAAAAAAAC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000379817.7. 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.484-25_484-5delGTTTTTTTTTTTGTTTTTTTT		splice_region intron	N/A	NP_001182177.2
	APTX	NM_001195249.2		c.484-25_484-5delGTTTTTTTTTTTGTTTTTTTT		splice_region intron	N/A	NP_001182178.1
	APTX	NM_001368995.1		c.484-25_484-5delGTTTTTTTTTTTGTTTTTTTT		splice_region 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.484-25_484-5delGTTTTTTTTTTTGTTTTTTTT		splice_region intron	N/A	ENSP00000369145.2
	APTX	ENST00000379819.6	TSL:1	c.484-25_484-5delGTTTTTTTTTTTGTTTTTTTT		splice_region intron	N/A	ENSP00000369147.2
	APTX	ENST00000463596.6	TSL:1	c.484-25_484-5delGTTTTTTTTTTTGTTTTTTTT		splice_region intron	N/A	ENSP00000419846.1

Frequencies

GnomAD3 genomes AF: 0.421 AC: 44470 AN: 105626 Hom.: 7126 Cov.: 0

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.436

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.443

GnomAD2 exomes AF: 0.263 AC: 38489 AN: 146242 AF XY: 0.261

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.303

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.266 AC: 311082 AN: 1171552 Hom.: 7475 AF XY: 0.261 AC XY: 152703 AN XY: 586162

African (AFR) AF: 0.189 AC: 4795 AN: 25432

American (AMR) AF: 0.220 AC: 6855 AN: 31152

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 6475 AN: 20866

East Asian (EAS) AF: 0.111 AC: 3929 AN: 35548

South Asian (SAS) AF: 0.137 AC: 9419 AN: 68740

European-Finnish (FIN) AF: 0.245 AC: 9541 AN: 38982

Middle Eastern (MID) AF: 0.271 AC: 912 AN: 3360

European-Non Finnish (NFE) AF: 0.286 AC: 256542 AN: 898394

Other (OTH) AF: 0.257 AC: 12614 AN: 49078

GnomAD4 genome AF: 0.421 AC: 44465 AN: 105628 Hom.: 7125 Cov.: 0 AF XY: 0.416 AC XY: 21038 AN XY: 50558

African (AFR) AF: 0.328 AC: 9345 AN: 28496

American (AMR) AF: 0.430 AC: 4525 AN: 10530

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1425 AN: 2720

East Asian (EAS) AF: 0.248 AC: 689 AN: 2780

South Asian (SAS) AF: 0.295 AC: 797 AN: 2698

European-Finnish (FIN) AF: 0.442 AC: 2512 AN: 5684

Middle Eastern (MID) AF: 0.435 AC: 87 AN: 200

European-Non Finnish (NFE) AF: 0.477 AC: 23992 AN: 50252

Other (OTH) AF: 0.442 AC: 656 AN: 1484

Alfa AF: 0.283 Hom.: 259

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (1)
-	-	1	Coenzyme Q10 deficiency, Oculomotor Apraxia Type (1)
-	-	1	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=98/2	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs200922655; hg19: chr9-32986032;