rs121908132

Positions:

• chr9-32974544-A-C
• chr9-32974544-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000379817.7(APTX):​c.788T>G​(p.Val263Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: APTX ENST00000379817.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.79

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain HIT (size 105) in uniprot entity APTX_HUMAN there are 31 pathogenic changes around while only 5 benign (86%) in ENST00000379817.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 9-32974544-A-C is Pathogenic according to our data. Variant chr9-32974544-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 4428.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-32974544-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APTX	NM_001195248.2	c.788T>G	p.Val263Gly	missense_variant	7/8	ENST00000379817.7	NP_001182177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APTX	ENST00000379817.7	c.788T>G	p.Val263Gly	missense_variant	7/8	1	NM_001195248.2	ENSP00000369145	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;.;.;.;D;.;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;T;T;T;.;T;.;.;T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;M;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.5	D;.;.;D;D;D;D;D;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;.;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 0.97	.;.;D;D;.;D;.;.;.;.
Vest4		0.64
MutPred		0.83		Gain of disorder (P = 0.0155);.;.;.;.;Gain of disorder (P = 0.0155);.;.;.;.;
MVP		1.0
MPC		0.41
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.98
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908132; hg19: chr9-32974542;