Genetic Variant NM_017825.3:c.316C>T (chr1-36091625-C-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_017825.3(ADPRS):c.316C>T(p.Gln106*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,444,284 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 (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

ADPRS
NM_017825.3 stop_gained

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.31

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-36091625-C-T is Pathogenic according to our data. Variant chr1-36091625-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 590299.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-36091625-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADPRS	NM_017825.3 link	c.316C>T	p.Gln106*	stop_gained	Exon 3 of 6	ENST00000373178.5	NP_060295.1	Q9NX46
ADPRS	XM_011541636.3 link	c.-147C>T		5_prime_UTR_variant	Exon 2 of 5		XP_011539938.1	B7ZAN4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADPRS	ENST00000373178.5 link	c.316C>T	p.Gln106*	stop_gained	Exon 3 of 6	1	NM_017825.3	ENSP00000362273.4		Q9NX46

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000831

AC:

AN:

240658

Hom.:

AF XY:

0.0000154

AC XY:

AN XY:

130214

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000346

AC:

AN:

1444284

Hom.:

Cov.:

AF XY:

0.00000419

AC XY:

AN XY:

716570

show subpopulations

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:

0.00000454

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000287

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:2

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2018

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

0.50

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.82

Vest4

0.24

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over