dbSNP rs34959427: MTPAP:c.781-54A>T (chr10-30326689-T-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.63

Publications

0 publications found

Variant links:

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)

MTPAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTPAP	NM_018109.4 link	c.781-54A>T		intron_variant	Intron 4 of 8	ENST00000263063.9	NP_060579.3	Q9NVV4-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MTPAP	ENST00000263063.9 link	c.781-54A>T	intron_variant	Intron 4 of 8	1	NM_018109.4	ENSP00000263063.3	Q9NVV4-1
MTPAP	ENST00000417581.1 link	c.586-54A>T	intron_variant	Intron 4 of 4	5		ENSP00000404392.1	Q5T852
MTPAP	ENST00000488290.5 link	n.2536-54A>T	intron_variant	Intron 12 of 16	2

Frequencies

GnomAD3 genomes

AF:

0.0313

AC:

4769

AN:

152180

Hom.:

103

Cov.:

show subpopulations

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

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

2313

4627

6940

9254

11567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1352

2704

4056

5408

6760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0313

AC:

4765

AN:

152298

Hom.:

103

Cov.:

AF XY:

0.0301

AC XY:

2239

AN XY:

74474

show subpopulations

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:

AN:

5194

South Asian (SAS)

AF:

0.0191

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0392

AC:

416

AN:

10600

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0450

AC:

3059

AN:

68032

Other (OTH)

AF:

0.0464

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

251

502

752

1003

1254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0413

Hom.:

Bravo

AF:

0.0309

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 23, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.1

(source)

DANN

Benign

0.71

PhyloP100

1.6

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over