10-30313640-C-T

Variant names:

• chr10-30313640-C-T
• rs771523018
• NM_018109.4:c.1718G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018109.4(MTPAP):​c.1718G>A​(p.Ser573Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MTPAP NM_018109.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.643
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027734786).

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.1718G>A	p.Ser573Asn	missense	Exon 9 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.1718G>A	p.Ser573Asn	missense	Exon 9 of 9	ENSP00000263063.3	Q9NVV4-1
	MTPAP	ENST00000958694.1		c.1769G>A	p.Ser590Asn	missense	Exon 10 of 10	ENSP00000628753.1
	MTPAP	ENST00000904049.1		c.1712G>A	p.Ser571Asn	missense	Exon 9 of 9	ENSP00000574108.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251382 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.0030
DANN	Benign	0.14
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.64
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.028
Sift	Benign	0.96	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.024
MutPred		0.18		Loss of glycosylation at S573 (P = 0.0165)
MVP		0.30
MPC		0.33
ClinPred		0.018	T
GERP RS		-7.8
Varity_R		0.018
gMVP		0.080
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs771523018; hg19: chr10-30602569; COSMIC: COSV99553818;