rs1047991

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018109.4(MTPAP):c.484C>T(p.Arg162Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,613,486 control chromosomes in the GnomAD database, including 58,995 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R162H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.25 ( 4671 hom., cov: 32)

Exomes 𝑓: 0.27 ( 54324 hom. )

Consequence

MTPAP
NM_018109.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.89

Publications

34 publications found

Variant links:

Genes affected

MTPAP (HGNC:25532): (mitochondrial poly(A) polymerase) The protein encoded by this gene is a member of the DNA polymerase type-B-like family. This enzyme synthesizes the 3' poly(A) tail of mitochondrial transcripts and plays a role in replication-dependent histone mRNA degradation.[provided by RefSeq, Jan 2011]

MTPAP Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
spastic ataxia 4
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

MTPAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037120283).

BP6

Variant 10-30340297-G-A is Benign according to our data. Variant chr10-30340297-G-A is described in ClinVar as Benign. ClinVar VariationId is 129624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTPAP	NM_018109.4 link	c.484C>T	p.Arg162Cys	missense_variant	Exon 3 of 9	ENST00000263063.9	NP_060579.3	Q9NVV4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MTPAP	ENST00000263063.9 link	c.484C>T	p.Arg162Cys	missense_variant	Exon 3 of 9	1	NM_018109.4	ENSP00000263063.3	Q9NVV4-1
MTPAP	ENST00000417581.1 link	c.289C>T	p.Arg97Cys	missense_variant	Exon 3 of 5	5		ENSP00000404392.1	Q5T852
MTPAP	ENST00000421701.1 link	c.370C>T	p.Arg124Cys	missense_variant	Exon 3 of 3	2		ENSP00000394118.1	Q5T851
MTPAP	ENST00000488290.5 link	n.2239C>T		non_coding_transcript_exon_variant	Exon 11 of 17	2

Frequencies

GnomAD3 genomes

AF:

0.247

AC:

37471

AN:

151920

Hom.:

4672

Cov.:

show subpopulations

Gnomad AFR

AF:

0.215

Gnomad AMI

AF:

0.252

Gnomad AMR

AF:

0.192

Gnomad ASJ

AF:

0.316

Gnomad EAS

AF:

0.228

Gnomad SAS

AF:

0.267

Gnomad FIN

AF:

0.221

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.278

Gnomad OTH

AF:

0.245

GnomAD2 exomes

AF:

0.246

AC:

61871

AN:

251446

AF XY:

0.253

show subpopulations

Gnomad AFR exome

AF:

0.215

Gnomad AMR exome

AF:

0.127

Gnomad ASJ exome

AF:

0.326

Gnomad EAS exome

AF:

0.227

Gnomad FIN exome

AF:

0.217

Gnomad NFE exome

AF:

0.281

Gnomad OTH exome

AF:

0.248

GnomAD4 exome

AF:

0.270

AC:

394303

AN:

1461448

Hom.:

54324

Cov.:

AF XY:

0.270

AC XY:

196564

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.212

AC:

7085

AN:

33472

American (AMR)

AF:

0.133

AC:

5953

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

8435

AN:

26132

East Asian (EAS)

AF:

0.244

AC:

9669

AN:

39694

South Asian (SAS)

AF:

0.269

AC:

23160

AN:

86250

European-Finnish (FIN)

AF:

0.219

AC:

11697

AN:

53418

Middle Eastern (MID)

AF:

0.265

AC:

1527

AN:

5766

European-Non Finnish (NFE)

AF:

0.280

AC:

310892

AN:

1111612

Other (OTH)

AF:

0.263

AC:

15885

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

16217

32434

48651

64868

81085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10298

20596

30894

41192

51490

<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:

0.246

AC:

37467

AN:

152038

Hom.:

4671

Cov.:

AF XY:

0.243

AC XY:

18018

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.215

AC:

8898

AN:

41468

American (AMR)

AF:

0.192

AC:

2932

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

1097

AN:

3472

East Asian (EAS)

AF:

0.228

AC:

1178

AN:

5160

South Asian (SAS)

AF:

0.267

AC:

1286

AN:

4818

European-Finnish (FIN)

AF:

0.221

AC:

2333

AN:

10542

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.278

AC:

18932

AN:

67990

Other (OTH)

AF:

0.245

AC:

517

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1461

2922

4383

5844

7305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

396

792

1188

1584

1980

<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:

0.268

Hom.:

21941

Bravo

AF:

0.241

TwinsUK

AF:

0.275

AC:

1019

ALSPAC

AF:

0.278

AC:

1072

ESP6500AA

AF:

0.212

AC:

935

ESP6500EA

AF:

0.288

AC:

2476

ExAC

AF:

0.250

AC:

30348

Asia WGS

AF:

0.252

AC:

876

AN:

3478

EpiCase

AF:

0.288

EpiControl

AF:

0.288

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 06, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Spastic ataxia 4

Benign:3

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 20, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.0070

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.014

T;.;.

Eigen

Benign

-2.6

Eigen_PC

Benign

-2.6

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.38

T;T;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.26

N;.;.

PhyloP100

-2.9

PrimateAI

Benign

0.19

PROVEAN

Benign

-0.64

N;N;N

REVEL

Benign

0.025

Sift

Benign

0.069

T;T;T

Sift4G

Benign

0.067

T;T;T

Polyphen

0.0010

B;.;B

Vest4

0.032

MPC

0.49

ClinPred

0.015

GERP RS

-10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.043

gMVP

0.30

Mutation Taster

=95/5

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over