10-30326689-T-A

Variant names:

• chr10-30326689-T-A
• rs34959427
• NM_018109.4:c.781-54A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018109.4(MTPAP):​c.781-54A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,379,008 control chromosomes in the GnomAD database, including 1,239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (103 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1136 hom.)
• Consequence: MTPAP NM_018109.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.63
• Publications: 0 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=-0.78).
• BP6: Variant 10-30326689-T-A is Benign according to our data. Variant chr10-30326689-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1212421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0313 (4765/152298) while in subpopulation NFE AF = 0.045 (3059/68032). AF 95% confidence interval is 0.0436. There are 103 homozygotes in GnomAd4. There are 2239 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 103 AR gene

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.781-54A>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.781-54A>T		intron	N/A	ENSP00000263063.3
	MTPAP	ENST00000417581.1	TSL:5	c.586-54A>T		intron	N/A	ENSP00000404392.1
	MTPAP	ENST00000488290.5	TSL:2	n.2536-54A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0313 AC: 4769 AN: 152180 Hom.: 103 Cov.: 33

Gnomad AFR AF: 0.00869

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0344

Gnomad ASJ AF: 0.0528

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0450

Gnomad OTH AF: 0.0468

GnomAD4 exome AF: 0.0398 AC: 48855 AN: 1226710 Hom.: 1136 AF XY: 0.0392 AC XY: 24381 AN XY: 621784

African (AFR) AF: 0.00804 AC: 228 AN: 28354

American (AMR) AF: 0.0268 AC: 1157 AN: 43218

Ashkenazi Jewish (ASJ) AF: 0.0501 AC: 1235 AN: 24668

East Asian (EAS) AF: 0.0000519 AC: 2 AN: 38530

South Asian (SAS) AF: 0.0194 AC: 1562 AN: 80662

European-Finnish (FIN) AF: 0.0409 AC: 2156 AN: 52720

Middle Eastern (MID) AF: 0.0272 AC: 127 AN: 4668

European-Non Finnish (NFE) AF: 0.0448 AC: 40392 AN: 901514

Other (OTH) AF: 0.0381 AC: 1996 AN: 52376

GnomAD4 genome AF: 0.0313 AC: 4765 AN: 152298 Hom.: 103 Cov.: 33 AF XY: 0.0301 AC XY: 2239 AN XY: 74474

African (AFR) AF: 0.00866 AC: 360 AN: 41566

American (AMR) AF: 0.0343 AC: 525 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0528 AC: 183 AN: 3466

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5194

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4826

European-Finnish (FIN) AF: 0.0392 AC: 416 AN: 10600

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0450 AC: 3059 AN: 68032

Other (OTH) AF: 0.0464 AC: 98 AN: 2114

Alfa AF: 0.0413 Hom.: 18

Bravo AF: 0.0309

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 23, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.1
DANN	Benign	0.71
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

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: rs34959427; hg19: chr10-30615618;