rs141493373

Variant names:

• chr9-32973556-T-A
• rs141493373
• NM_001195248.2:c.971A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001195248.2(APTX):​c.971A>T​(p.Gln324Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00199 in 1,614,116 control chromosomes in the GnomAD database, including 5 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 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (4 hom.)
• Consequence: APTX NM_001195248.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:8
• Conservation: PhyloP100: 6.73
• 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013023466).
• BP6: Variant 9-32973556-T-A is Benign according to our data. Variant chr9-32973556-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 136416.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00118 (179/152238) while in subpopulation NFE AF = 0.00221 (150/67996). AF 95% confidence interval is 0.00192. There are 1 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.971A>T	p.Gln324Leu	missense	Exon 8 of 8	NP_001182177.2	Q7Z2E3-7
	APTX	NM_001195249.2		c.971A>T	p.Gln324Leu	missense	Exon 8 of 8	NP_001182178.1	Q7Z2E3-7
	APTX	NM_001368995.1		c.971A>T	p.Gln324Leu	missense	Exon 8 of 8	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.971A>T	p.Gln324Leu	missense	Exon 8 of 8	ENSP00000369145.2	Q7Z2E3-7
	APTX	ENST00000379819.6	TSL:1	c.971A>T	p.Gln324Leu	missense	Exon 9 of 9	ENSP00000369147.2	Q7Z2E3-7
	APTX	ENST00000463596.6	TSL:1	c.971A>T	p.Gln324Leu	missense	Exon 8 of 8	ENSP00000419846.1	Q7Z2E3-7

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00113 AC: 283 AN: 251214 AF XY: 0.00118

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00217

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00207 AC: 3031 AN: 1461878 Hom.: 4 Cov.: 32 AF XY: 0.00197 AC XY: 1433 AN XY: 727238

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53414

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00263 AC: 2926 AN: 1112006

Other (OTH) AF: 0.000944 AC: 57 AN: 60396

GnomAD4 genome AF: 0.00118 AC: 179 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74432

African (AFR) AF: 0.000409 AC: 17 AN: 41556

American (AMR) AF: 0.000393 AC: 6 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00221 AC: 150 AN: 67996

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00110

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00102 AC: 124

EpiCase AF: 0.00256

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	2	1	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (3)
-	-	3	not specified (3)
-	-	1	APTX-related disorder (1)
-	1	-	Coenzyme Q10 deficiency, Oculomotor Apraxia Type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.0021
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.7
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.25
Sift	Benign	0.28	T
Sift4G	Benign	0.72	T
Polyphen		0.022	B
Vest4		0.36
MVP		0.99
MPC		0.077
ClinPred		0.024	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.56
Mutation Taster		=42/58	disease causing

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: rs141493373; hg19: chr9-32973554;