rs1057517678

Positions:

• chr4-105386625-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_176869.3(PPA2):​c.881A>C​(p.Gln294Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q294R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPA2 NM_176869.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.76

Genes affected

PPA2 (HGNC:28883): (inorganic pyrophosphatase 2) The protein encoded by this gene is localized to the mitochondrion, is highly similar to members of the inorganic pyrophosphatase (PPase) family, and contains the signature sequence essential for the catalytic activity of PPase. PPases catalyze the hydrolysis of pyrophosphate to inorganic phosphate, which is important for the phosphate metabolism of cells. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-105386625-T-G is Pathogenic according to our data. Variant chr4-105386625-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 372221.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPA2	NM_176869.3	c.881A>C	p.Gln294Pro	missense_variant	10/12	ENST00000341695.10
PPA2	NM_006903.4	c.794A>C	p.Gln265Pro	missense_variant	9/11
PPA2	NM_176866.2	c.575A>C	p.Gln192Pro	missense_variant	6/8
PPA2	NM_176867.3	c.383A>C	p.Gln128Pro	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPA2	ENST00000341695.10	c.881A>C	p.Gln294Pro	missense_variant	10/12	1	NM_176869.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Sudden cardiac failure, infantile Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.00083	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.043	T;.;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.044	D;D;T;D
Polyphen		0.43	B;B;D;.
Vest4		0.90
MutPred		0.44		Loss of catalytic residue at Q294 (P = 0.0276);.;.;.;
MVP		0.59
MPC		0.39
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.41
gMVP		0.79

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

LitVar

Other links and lift over

dbSNP: rs1057517678; hg19: chr4-106307782;