rs17855116

Positions:

• chr10-30313721-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_018109.4(MTPAP):​c.1637G>A​(p.Ser546Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,614,140 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (10 hom.)
• Consequence: MTPAP NM_018109.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0500

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035369396).
• BP6: Variant 10-30313721-C-T is Benign according to our data. Variant chr10-30313721-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 378180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-30313721-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTPAP	NM_018109.4	c.1637G>A	p.Ser546Asn	missense_variant	9/9	ENST00000263063.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTPAP	ENST00000263063.9	c.1637G>A	p.Ser546Asn	missense_variant	9/9	1	NM_018109.4	P1
MTPAP	ENST00000488290.5	n.3392G>A		non_coding_transcript_exon_variant	17/17	2

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 313 AN: 152148 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00247 AC: 620 AN: 251390 Hom.: 7 AF XY: 0.00236 AC XY: 321 AN XY: 135868

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00843

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0161

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00162 AC: 2368 AN: 1461874 Hom.: 10 Cov.: 31 AF XY: 0.00162 AC XY: 1176 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00830

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0147

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00206 AC: 313 AN: 152266 Hom.: 2 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74442

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0128

Gnomad4 NFE AF: 0.00196

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00217 Hom.: 1

Bravo AF: 0.000786

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00219 AC: 266

EpiCase AF: 0.00104

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2015	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

MTPAP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.5
DANN	Benign	0.39
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.20	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.016
Sift	Benign	0.39	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.020
MVP		0.28
MPC		0.33
ClinPred		0.0064	T
GERP RS		-2.2
Varity_R		0.016
gMVP		0.094

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: rs17855116; hg19: chr10-30602650;