chr1-36091274-T-A

Variant names:

• chr1-36091274-T-A
• NM_017825.3:c.242T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_017825.3(ADPRS):​c.242T>A​(p.Met81Lys) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADPRS NM_017825.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017825.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADPRS	NM_017825.3	MANE Select	c.242T>A	p.Met81Lys	missense	Exon 2 of 6	NP_060295.1	Q9NX46

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADPRS	ENST00000373178.5	TSL:1 MANE Select	c.242T>A	p.Met81Lys	missense	Exon 2 of 6	ENSP00000362273.4	Q9NX46
	ADPRS	ENST00000896939.1		c.239T>A	p.Met80Lys	missense	Exon 2 of 6	ENSP00000566998.1
	ADPRS	ENST00000932449.1		c.230T>A	p.Met77Lys	missense	Exon 2 of 6	ENSP00000602508.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.89		Gain of ubiquitination at M81 (P = 0.023)
MVP		0.61
MPC		1.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
gMVP		0.96
Mutation Taster		=9/91	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

hg19: chr1-36556875;