10-30316175-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018109.4(MTPAP):c.1255T>A(p.Cys419Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C419G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MTPAP NM_018109.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.11

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTPAP	NM_018109.4	c.1255T>A	p.Cys419Ser	missense_variant	7/9	ENST00000263063.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTPAP	ENST00000263063.9	c.1255T>A	p.Cys419Ser	missense_variant	7/9	1	NM_018109.4	P1
MTPAP	ENST00000488290.5	n.3010T>A		non_coding_transcript_exon_variant	15/17	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251386 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS 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: 0.00000342 AC: 5 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.079	T
Polyphen		1.0	D
Vest4		0.91
MutPred		0.63		Gain of disorder (P = 0.0349);
MVP		0.71
MPC		1.3
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.76
gMVP		0.84

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: rs17857517; hg19: chr10-30605104;