10-30313751-G-C

Position:

• chr10-30313751-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_018109.4(MTPAP):​c.1607C>G​(p.Pro536Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000691 in 1,614,096 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (1 hom.)
• Consequence: MTPAP NM_018109.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.477

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.00920409).
• BP6: Variant 10-30313751-G-C is Benign according to our data. Variant chr10-30313751-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447741.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTPAP	NM_018109.4	c.1607C>G	p.Pro536Arg	missense_variant	9/9	ENST00000263063.9	NP_060579.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTPAP	ENST00000263063.9	c.1607C>G	p.Pro536Arg	missense_variant	9/9	1	NM_018109.4	ENSP00000263063.3
MTPAP	ENST00000488290.5	n.3362C>G		non_coding_transcript_exon_variant	17/17	2

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000605 AC: 152 AN: 251414 Hom.: 1 AF XY: 0.000699 AC XY: 95 AN XY: 135886

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000756

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000720 AC: 1053 AN: 1461856 Hom.: 1 Cov.: 31 AF XY: 0.000773 AC XY: 562 AN XY: 727236

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00121

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000787

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74448

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000609 Hom.: 0

Bravo AF: 0.000336

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000535 AC: 65

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 09, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2017	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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.6
DANN	Benign	0.24
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.016
Sift	Benign	0.57	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.042
MVP		0.15
MPC		0.38
ClinPred		0.0010	T
GERP RS		-0.68
Varity_R		0.020
gMVP		0.16

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: rs147174746; hg19: chr10-30602680;