rs200626873

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_017825.3(ADPRS):c.530C>T(p.Ser177Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000757 in 1,452,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

ADPRS
NM_017825.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.77

Publications

3 publications found

Variant links:

Genes affected

ADPRS (HGNC:21304): (ADP-ribosylserine hydrolase) This gene encodes a member of the ADP-ribosylglycohydrolase family. The encoded enzyme catalyzes the removal of ADP-ribose from ADP-ribosylated proteins. This enzyme localizes to the mitochondria, in addition to the nucleus and cytoplasm.[provided by RefSeq, Feb 2009]

ADPRS Gene-Disease associations (from GenCC):

neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ADPRS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.783

PP5

Variant 1-36091923-C-T is Pathogenic according to our data. Variant chr1-36091923-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 590302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADPRS	NM_017825.3 link	c.530C>T	p.Ser177Leu	missense_variant	Exon 4 of 6	ENST00000373178.5	NP_060295.1	Q9NX46
ADPRS	XM_011541636.3 link	c.68C>T	p.Ser23Leu	missense_variant	Exon 3 of 5		XP_011539938.1	B7ZAN4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADPRS	ENST00000373178.5 link	c.530C>T	p.Ser177Leu	missense_variant	Exon 4 of 6	1	NM_017825.3	ENSP00000362273.4		Q9NX46

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000405

AC:

AN:

246898

AF XY:

0.00000750

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:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000757

AC:

AN:

1452554

Hom.:

Cov.:

AF XY:

0.00000832

AC XY:

AN XY:

721072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33346

American (AMR)

AF:

0.00

AC:

AN:

44158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25730

East Asian (EAS)

AF:

0.00

AC:

AN:

39472

South Asian (SAS)

AF:

0.00

AC:

AN:

85526

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00000905

AC:

AN:

1105402

Other (OTH)

AF:

0.0000167

AC:

AN:

59976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000314

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures

Pathogenic:3

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been previously reported as a homozygous change in patients with Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome (PMID: 30100084). The c.530C>T (p.Ser177Leu) variant is located in the ADP-ribosyl-glycohydrolase, which is a known hotspot domain for pathogenic variations associated with Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome (PMID: 30100084). The c.530C>T (p.Ser177Leu) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/246898) and is absent in the homozygous state, thus it is presumed to be rare. The c.530C>T (p.Ser177Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.530C>T (p.Ser177Leu) variant is classified as Likely Pathogenic. -

Nov 08, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 07, 2019

Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant results in the substitution of the highly-conserved serine at position 177 for a leucine. This variant localizes to coding exon 4 of the ADPRHL2 gene (6 coding exons in total; NM_017825.3), and is localized in a critical alpha-helical loop within the ADP-ribosylhydrolase domain (PMID: 30100084). In silico analysis predicts this change to be deleterious to the structure and/or function of the protein (possibly damaging by Polyphen2 and deleterious by SIFT). This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (1/246,898), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in a homozygous state in two siblings with progressive weakness, seizures and deteriorating speech and motor development from a consanguineous Iranian family. Although functional studies of the variant and studies of patient cells were not performed, it was predicted to result in a loss of function (PMID: 30100084). Given this evidence, this variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.014

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-0.82

MutationAssessor

Pathogenic

3.5

PhyloP100

6.8

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.34

Sift

Benign

0.13

Sift4G

Benign

0.11

Polyphen

0.99

Vest4

0.76

MutPred

0.63

Loss of disorder (P = 0.0488);

MVP

0.61

MPC

0.60

ClinPred

0.98

GERP RS

5.5

Varity_R

0.77

gMVP

0.77

Mutation Taster

=51/49

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over