rs34778324

Variant names:

• chr9-32987596-G-T
• rs34778324
• NM_001195248.2:c.431C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001195248.2(APTX):​c.431C>A​(p.Ser144Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00774 in 1,614,140 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (49 hom.)
• Consequence: APTX NM_001195248.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.36
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061478317).
• BP6: Variant 9-32987596-G-T is Benign according to our data. Variant chr9-32987596-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00553 (842/152330) while in subpopulation NFE AF = 0.00923 (628/68026). AF 95% confidence interval is 0.00863. There are 7 homozygotes in GnomAd4. There are 366 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.431C>A	p.Ser144Tyr	missense	Exon 4 of 8	NP_001182177.2	Q7Z2E3-7
	APTX	NM_001195249.2		c.431C>A	p.Ser144Tyr	missense	Exon 4 of 8	NP_001182178.1	Q7Z2E3-7
	APTX	NM_001368995.1		c.431C>A	p.Ser144Tyr	missense	Exon 4 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.431C>A	p.Ser144Tyr	missense	Exon 4 of 8	ENSP00000369145.2	Q7Z2E3-7
	APTX	ENST00000379819.6	TSL:1	c.431C>A	p.Ser144Tyr	missense	Exon 5 of 9	ENSP00000369147.2	Q7Z2E3-7
	APTX	ENST00000463596.6	TSL:1	c.431C>A	p.Ser144Tyr	missense	Exon 4 of 8	ENSP00000419846.1	Q7Z2E3-7

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 842 AN: 152212 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00923

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00562 AC: 1412 AN: 251332 AF XY: 0.00554

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00431

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00980

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.00797 AC: 11654 AN: 1461810 Hom.: 49 Cov.: 32 AF XY: 0.00772 AC XY: 5617 AN XY: 727212

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.00523 AC: 234 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00291 AC: 155 AN: 53344

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.00966 AC: 10743 AN: 1112004

Other (OTH) AF: 0.00666 AC: 402 AN: 60396

GnomAD4 genome AF: 0.00553 AC: 842 AN: 152330 Hom.: 7 Cov.: 32 AF XY: 0.00491 AC XY: 366 AN XY: 74500

African (AFR) AF: 0.00166 AC: 69 AN: 41578

American (AMR) AF: 0.00536 AC: 82 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00923 AC: 628 AN: 68026

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00831 Hom.: 18

Bravo AF: 0.00591

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00575 AC: 698

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00954

EpiControl AF: 0.00996

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	not provided (5)
-	-	1	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	9.2
DANN	Benign	0.66
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.4
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.32
Sift	Benign	0.045	D
Sift4G	Benign	0.12	T
Polyphen		0.095	B
Vest4		0.23
MVP		0.68
MPC		0.095
ClinPred		0.0020	T
GERP RS		-0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.10
gMVP		0.27
Mutation Taster		=94/6	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: rs34778324; hg19: chr9-32987594; COSMIC: COSV107370356; COSMIC: COSV107370356;