NM_017825.3:c.136G>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_017825.3(ADPRS):c.136G>T(p.Val46Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000319 in 1,474,224 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V46L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

ADPRS
NM_017825.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.83

Publications

1 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: Labcorp Genetics (formerly Invitae), G2P

ADPRS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000325 (43/1321890) while in subpopulation MID AF = 0.00112 (6/5354). AF 95% confidence interval is 0.000487. There are 0 homozygotes in GnomAdExome4. There are 20 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.136G>T	p.Val46Phe	missense	Exon 1 of 6	NP_060295.1	Q9NX46

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADPRS	ENST00000373178.5	TSL:1 MANE Select	c.136G>T	p.Val46Phe	missense	Exon 1 of 6	ENSP00000362273.4	Q9NX46
ADPRS	ENST00000896939.1		c.136G>T	p.Val46Phe	missense	Exon 1 of 6	ENSP00000566998.1
ADPRS	ENST00000932449.1		c.136G>T	p.Val46Phe	missense	Exon 1 of 6	ENSP00000602508.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000135

AC:

AN:

73876

AF XY:

0.0000248

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000325

AC:

AN:

1321890

Hom.:

Cov.:

AF XY:

0.0000308

AC XY:

AN XY:

648448

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26256

American (AMR)

AF:

0.00

AC:

AN:

22986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19512

East Asian (EAS)

AF:

0.00

AC:

AN:

31912

South Asian (SAS)

AF:

0.000150

AC:

AN:

66832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45608

Middle Eastern (MID)

AF:

0.00112

AC:

AN:

5354

European-Non Finnish (NFE)

AF:

0.0000210

AC:

AN:

1048972

Other (OTH)

AF:

0.0000918

AC:

AN:

54458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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

AF:

0.0000263

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41586

American (AMR)

AF:

0.000131

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000893

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

-0.0098

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.61

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.72

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.3

PhyloP100

2.8

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.6

REVEL

Benign

0.20

Sift

Uncertain

0.0070

Sift4G

Benign

0.31

Polyphen

0.98

Vest4

0.62

MVP

0.69

MPC

0.92

ClinPred

0.76

GERP RS

4.7

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.69

gMVP

0.64

Mutation Taster

=27/73

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over