rs540994

Variant names:

• chr10-30311297-A-C
• rs540994
• NM_018109.4:c.*2312T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018109.4(MTPAP):​c.*2312T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 152,052 control chromosomes in the GnomAD database, including 17,011 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.45 (17011 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: MTPAP NM_018109.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.308
• Publications: 9 publications found

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)

ENSG00000285824 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTPAP	NM_018109.4	c.*2312T>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000263063.9	NP_060579.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTPAP	ENST00000263063.9	c.*2312T>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_018109.4	ENSP00000263063.3
ENSG00000285824	ENST00000650129.1	n.853+463A>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68932 AN: 151932 Hom.: 17010 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.490

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.453 AC: 68944 AN: 152052 Hom.: 17011 Cov.: 32 AF XY: 0.450 AC XY: 33428 AN XY: 74302

African (AFR) AF: 0.278 AC: 11534 AN: 41454

American (AMR) AF: 0.545 AC: 8329 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1855 AN: 3472

East Asian (EAS) AF: 0.142 AC: 736 AN: 5188

South Asian (SAS) AF: 0.446 AC: 2151 AN: 4822

European-Finnish (FIN) AF: 0.487 AC: 5142 AN: 10550

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.553 AC: 37578 AN: 67972

Other (OTH) AF: 0.485 AC: 1024 AN: 2112

Alfa AF: 0.510 Hom.: 2615

Bravo AF: 0.450

Asia WGS AF: 0.301 AC: 1049 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.67
DANN	Benign	0.64
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs540994; hg19: chr10-30600226;