rs200626873

chr1-36091923-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.77

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 590302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-36091923-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADPRS	NM_017825.3	c.530C>T	p.Ser177Leu	missense_variant	4/6	ENST00000373178.5
ADPRS	XM_011541636.3	c.68C>T	p.Ser23Leu	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADPRS	ENST00000373178.5	c.530C>T	p.Ser177Leu	missense_variant	4/6	1	NM_017825.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246898 Hom.: 0 AF XY: 0.00000750 AC XY: 1 AN XY: 133390

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 SAS 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: 11 AN: 1452554 Hom.: 0 Cov.: 31 AF XY: 0.00000832 AC XY: 6 AN XY: 721072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000905

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000314 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 08, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	Oct 07, 2019	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	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.34
Sift	Benign	0.13	T
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.76
MutPred		0.63		Loss of disorder (P = 0.0488);
MVP		0.61
MPC		0.60
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.77
gMVP		0.77

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: rs200626873; hg19: chr1-36557524; COSMIC: COSV99255576; COSMIC: COSV99255576;