rs1047988

Variant names:

• chr10-30340207-G-A
• rs1047988
• NM_018109.4:c.555+19C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018109.4(MTPAP):​c.555+19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 1,569,076 control chromosomes in the GnomAD database, including 57,163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4871 hom., cov: 33)
  • Exomes 𝑓: 0.27 (52292 hom.)
• Consequence: MTPAP NM_018109.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.653
• Publications: 8 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-30340207-G-A is Benign according to our data. Variant chr10-30340207-G-A is described in ClinVar as Benign. ClinVar VariationId is 138281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018109.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTPAP	NM_018109.4	MANE Select	c.555+19C>T		intron	N/A	NP_060579.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTPAP	ENST00000263063.9	TSL:1 MANE Select	c.555+19C>T		intron	N/A	ENSP00000263063.3
	MTPAP	ENST00000421701.1	TSL:2	c.*7C>T		3_prime_UTR	Exon 3 of 3	ENSP00000394118.1
	MTPAP	ENST00000417581.1	TSL:5	c.360+19C>T		intron	N/A	ENSP00000404392.1

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38362 AN: 151916 Hom.: 4872 Cov.: 33

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.252

GnomAD2 exomes AF: 0.247 AC: 61829 AN: 250128 AF XY: 0.254

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.325

Gnomad EAS exome AF: 0.230

Gnomad FIN exome AF: 0.216

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.269 AC: 380502 AN: 1417042 Hom.: 52292 Cov.: 28 AF XY: 0.269 AC XY: 190540 AN XY: 707564

African (AFR) AF: 0.230 AC: 7476 AN: 32526

American (AMR) AF: 0.134 AC: 5989 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 8343 AN: 25886

East Asian (EAS) AF: 0.245 AC: 9676 AN: 39438

South Asian (SAS) AF: 0.269 AC: 22929 AN: 85354

European-Finnish (FIN) AF: 0.219 AC: 11652 AN: 53280

Middle Eastern (MID) AF: 0.263 AC: 1493 AN: 5668

European-Non Finnish (NFE) AF: 0.278 AC: 297449 AN: 1071252

Other (OTH) AF: 0.263 AC: 15495 AN: 59002

GnomAD4 genome AF: 0.252 AC: 38358 AN: 152034 Hom.: 4871 Cov.: 33 AF XY: 0.248 AC XY: 18455 AN XY: 74298

African (AFR) AF: 0.233 AC: 9667 AN: 41440

American (AMR) AF: 0.196 AC: 2993 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1096 AN: 3466

East Asian (EAS) AF: 0.232 AC: 1202 AN: 5176

South Asian (SAS) AF: 0.267 AC: 1289 AN: 4822

European-Finnish (FIN) AF: 0.222 AC: 2344 AN: 10560

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.279 AC: 18940 AN: 67980

Other (OTH) AF: 0.252 AC: 532 AN: 2110

Alfa AF: 0.267 Hom.: 2851

Bravo AF: 0.248

Asia WGS AF: 0.252 AC: 878 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	Spastic ataxia 4 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.6
DANN	Benign	0.62
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1047988; hg19: chr10-30629136; COSMIC: COSV107309309;