rs267606665

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_ModeratePP5_Moderate

The NM_001195248.2(APTX):c.668T>C(p.Leu223Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L223F) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

APTX
NM_001195248.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.32

Publications

6 publications found

Variant links:

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

APTX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-32984734-G-A is described in CliVar as Pathogenic. Clinvar id is 214128.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

PP5

Variant 9-32984733-A-G is Pathogenic according to our data. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984733-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4433.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APTX	NM_001195248.2 link	c.668T>C	p.Leu223Pro	missense_variant	Exon 6 of 8	ENST00000379817.7	NP_001182177.2	Q7Z2E3-7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APTX	ENST00000379817.7 link	c.668T>C	p.Leu223Pro	missense_variant	Exon 6 of 8	1	NM_001195248.2	ENSP00000369145.2		Q7Z2E3-7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251456

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia

Pathogenic:2

Jul 12, 2021

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

.;.;.;.;.;D;.;.;.;.;D;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D;.;D;.;.;D;D;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

H;.;.;.;.;H;.;.;.;.;.;.

PhyloP100

9.3

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.8

D;.;.;D;D;D;D;D;D;.;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.;.;D;D;D;D;D;D;.;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;D;.;.

Polyphen

1.0

.;.;D;D;.;D;.;.;.;.;.;D

Vest4

0.99

MutPred

0.77

Gain of disorder (P = 0.0098);.;.;.;.;Gain of disorder (P = 0.0098);.;.;.;.;.;.;

MVP

0.97

MPC

0.45

ClinPred

1.0

GERP RS

5.6

Varity_R

0.99

gMVP

0.92

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over