chr10-30316175-A-C

Variant names:

• chr10-30316175-A-C
• rs17857517
• NM_018109.4:c.1255T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018109.4(MTPAP):​c.1255T>G​(p.Cys419Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C419Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MTPAP NM_018109.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.11
• Publications: 1 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

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.1255T>G	p.Cys419Gly	missense	Exon 7 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.1255T>G	p.Cys419Gly	missense	Exon 7 of 9	ENSP00000263063.3	Q9NVV4-1
	MTPAP	ENST00000958694.1		c.1306T>G	p.Cys436Gly	missense	Exon 8 of 10	ENSP00000628753.1
	MTPAP	ENST00000904049.1		c.1249T>G	p.Cys417Gly	missense	Exon 7 of 9	ENSP00000574108.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.025	T
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-10	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.085	T
Polyphen		1.0	D
Vest4		0.92
MutPred		0.52		Loss of stability (P = 0.0201)
MVP		0.74
MPC		1.3
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.84
gMVP		0.87
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs17857517; hg19: chr10-30605104;