NM_001195248.2:c.788T>C

Variant names:

• chr9-32974544-A-G
• rs121908132
• NM_001195248.2:c.788T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001195248.2(APTX):​c.788T>C​(p.Val263Ala) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V263G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: APTX NM_001195248.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.79
• Publications: 11 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-32974544-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4428.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APTX	NM_001195248.2	c.788T>C	p.Val263Ala	missense_variant	Exon 7 of 8	ENST00000379817.7	NP_001182177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APTX	ENST00000379817.7	c.788T>C	p.Val263Ala	missense_variant	Exon 7 of 8	1	NM_001195248.2	ENSP00000369145.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;.;.;.;D;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.;M;.;.;.;.
PhyloP100		8.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.6	D;.;.;D;D;D;D;D;D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0090	D;.;.;D;D;D;D;D;D;.
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 0.94, 1.0	.;.;D;P;.;D;.;.;.;.
Vest4		0.96
MutPred		0.77		Gain of disorder (P = 0.0725);.;.;.;.;Gain of disorder (P = 0.0725);.;.;.;.;
MVP		0.98
MPC		0.36
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.75
gMVP		0.81
Mutation Taster		=30/70	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: rs121908132; hg19: chr9-32974542;