rs1047991

chr10-30340297-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/19 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.89

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 129624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-30340297-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
MTPAP	NM_018109.4	c.484C>T	p.Arg162Cys	missense_variant	3/9	ENST00000263063.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTPAP	ENST00000263063.9	c.484C>T	p.Arg162Cys	missense_variant	3/9	1	NM_018109.4	P1
MTPAP	ENST00000417581.1	c.289C>T	p.Arg97Cys	missense_variant	3/5	5
MTPAP	ENST00000421701.1	c.370C>T	p.Arg124Cys	missense_variant	3/3	2
MTPAP	ENST00000488290.5	n.2239C>T		non_coding_transcript_exon_variant	11/17	2

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37471 AN: 151920 Hom.: 4672 Cov.: 32

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

GnomAD3 exomes AF: 0.246 AC: 61871 AN: 251446 Hom.: 8129 AF XY: 0.253 AC XY: 34380 AN XY: 135894

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 SAS exome AF: 0.271

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.: 37 AF XY: 0.270 AC XY: 196564 AN XY: 727036

Gnomad4 AFR exome AF: 0.212

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.323

Gnomad4 EAS exome AF: 0.244

Gnomad4 SAS exome AF: 0.269

Gnomad4 FIN exome AF: 0.219

Gnomad4 NFE exome AF: 0.280

Gnomad4 OTH exome AF: 0.263

GnomAD4 genome AF: 0.246 AC: 37467 AN: 152038 Hom.: 4671 Cov.: 32 AF XY: 0.243 AC XY: 18018 AN XY: 74296

Gnomad4 AFR AF: 0.215

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.267

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.278

Gnomad4 OTH AF: 0.245

Alfa AF: 0.274 Hom.: 14977

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2013	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

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.0070
Dann	Benign	0.60
DEOGEN2	Benign	0.014	T;.;.
Eigen	Benign	-2.6
Eigen_PC	Benign	-2.6
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.38	T;T;T
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.26	N;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.19	T
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	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.30

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: rs1047991; hg19: chr10-30629226; COSMIC: COSV53933076;