rs1047991

Variant names:

• chr10-30340297-G-A
• rs1047991
• NM_018109.4:c.484C>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.484C>T​(p.Arg162Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,613,486 control chromosomes in the GnomAD database, including 58,995 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R162G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.25 (4671 hom., cov: 32)
  • Exomes 𝑓: 0.27 (54324 hom.)
• Consequence: MTPAP NM_018109.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.89
• Publications: 34 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 (MetaRNN=0.0037120283).
• BP6: Variant 10-30340297-G-A is Benign according to our data. Variant chr10-30340297-G-A is described in ClinVar as Benign. ClinVar VariationId is 129624.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTPAP	NM_018109.4	MANE Select	c.484C>T	p.Arg162Cys	missense	Exon 3 of 9	NP_060579.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTPAP	ENST00000263063.9	TSL:1 MANE Select	c.484C>T	p.Arg162Cys	missense	Exon 3 of 9	ENSP00000263063.3	Q9NVV4-1
	MTPAP	ENST00000958694.1		c.535C>T	p.Arg179Cys	missense	Exon 4 of 10	ENSP00000628753.1
	MTPAP	ENST00000904049.1		c.484C>T	p.Arg162Cys	missense	Exon 3 of 9	ENSP00000574108.1

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37471 AN: 151920 Hom.: 4672 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.245

GnomAD2 exomes AF: 0.246 AC: 61871 AN: 251446 AF XY: 0.253

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.217

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.270 AC: 394303 AN: 1461448 Hom.: 54324 Cov.: 37 AF XY: 0.270 AC XY: 196564 AN XY: 727036

African (AFR) AF: 0.212 AC: 7085 AN: 33472

American (AMR) AF: 0.133 AC: 5953 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 8435 AN: 26132

East Asian (EAS) AF: 0.244 AC: 9669 AN: 39694

South Asian (SAS) AF: 0.269 AC: 23160 AN: 86250

European-Finnish (FIN) AF: 0.219 AC: 11697 AN: 53418

Middle Eastern (MID) AF: 0.265 AC: 1527 AN: 5766

European-Non Finnish (NFE) AF: 0.280 AC: 310892 AN: 1111612

Other (OTH) AF: 0.263 AC: 15885 AN: 60380

GnomAD4 genome AF: 0.246 AC: 37467 AN: 152038 Hom.: 4671 Cov.: 32 AF XY: 0.243 AC XY: 18018 AN XY: 74296

African (AFR) AF: 0.215 AC: 8898 AN: 41468

American (AMR) AF: 0.192 AC: 2932 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1097 AN: 3472

East Asian (EAS) AF: 0.228 AC: 1178 AN: 5160

South Asian (SAS) AF: 0.267 AC: 1286 AN: 4818

European-Finnish (FIN) AF: 0.221 AC: 2333 AN: 10542

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

European-Non Finnish (NFE) AF: 0.278 AC: 18932 AN: 67990

Other (OTH) AF: 0.245 AC: 517 AN: 2106

Alfa AF: 0.268 Hom.: 21941

Bravo AF: 0.241

TwinsUK AF: 0.275 AC: 1019

ALSPAC AF: 0.278 AC: 1072

ESP6500AA AF: 0.212 AC: 935

ESP6500EA AF: 0.288 AC: 2476

ExAC AF: 0.250 AC: 30348

Asia WGS AF: 0.252 AC: 876 AN: 3478

EpiCase AF: 0.288

EpiControl AF: 0.288

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0070
DANN	Benign	0.60
DEOGEN2	Benign	0.014	T
Eigen	Benign	-2.6
Eigen_PC	Benign	-2.6
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.26	N
PhyloP100		-2.9
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.025
Sift	Benign	0.069	T
Sift4G	Benign	0.067	T
Polyphen		0.0010	B
Vest4		0.032
MPC		0.49
ClinPred		0.015	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.30
Mutation Taster		=95/5	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: rs1047991; hg19: chr10-30629226; COSMIC: COSV53933076;