rs140888559

Variant names:

• chr9-32986001-C-T
• rs140888559
• NM_001195248.2:c.513G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001195248.2(APTX):​c.513G>A​(p.Leu171Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000668 in 1,489,068 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00068 (1 hom.)
• Consequence: APTX NM_001195248.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.507
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 9-32986001-C-T is Benign according to our data. Variant chr9-32986001-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262911.
• BP7: Synonymous conserved (PhyloP=0.507 with no splicing effect.

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.513G>A	p.Leu171Leu	synonymous	Exon 5 of 8	NP_001182177.2
	APTX	NM_001195249.2		c.513G>A	p.Leu171Leu	synonymous	Exon 5 of 8	NP_001182178.1
	APTX	NM_001368995.1		c.513G>A	p.Leu171Leu	synonymous	Exon 5 of 8	NP_001355924.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APTX	ENST00000379817.7	TSL:1 MANE Select	c.513G>A	p.Leu171Leu	synonymous	Exon 5 of 8	ENSP00000369145.2
	APTX	ENST00000379819.6	TSL:1	c.513G>A	p.Leu171Leu	synonymous	Exon 6 of 9	ENSP00000369147.2
	APTX	ENST00000463596.6	TSL:1	c.513G>A	p.Leu171Leu	synonymous	Exon 5 of 8	ENSP00000419846.1

Frequencies

GnomAD3 genomes AF: 0.000589 AC: 76 AN: 129132 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000360

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: 0.000981

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000310 AC: 77 AN: 248714 AF XY: 0.000327

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.000263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000541

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000675 AC: 918 AN: 1359936 Hom.: 1 Cov.: 34 AF XY: 0.000646 AC XY: 438 AN XY: 678016

African (AFR) AF: 0.000102 AC: 3 AN: 29502

American (AMR) AF: 0.000306 AC: 13 AN: 42418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23586

East Asian (EAS) AF: 0.00 AC: 0 AN: 32224

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3754

European-Non Finnish (NFE) AF: 0.000828 AC: 863 AN: 1042664

Other (OTH) AF: 0.000700 AC: 38 AN: 54258

GnomAD4 genome AF: 0.000589 AC: 76 AN: 129132 Hom.: 0 Cov.: 28 AF XY: 0.000526 AC XY: 32 AN XY: 60888

African (AFR) AF: 0.000271 AC: 9 AN: 33210

American (AMR) AF: 0.000360 AC: 4 AN: 11110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3340

East Asian (EAS) AF: 0.00 AC: 0 AN: 4234

South Asian (SAS) AF: 0.00 AC: 0 AN: 3938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.000981 AC: 63 AN: 64222

Other (OTH) AF: 0.00 AC: 0 AN: 1740

Alfa AF: 0.000584 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	1	-	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.95
PhyloP100		0.51
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs140888559; hg19: chr9-32985999;