chr4-105386625-T-C

Variant names:

• chr4-105386625-T-C
• rs1057517678
• NM_176869.3:c.881A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_176869.3(PPA2):​c.881A>G​(p.Gln294Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. Q294P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPA2 NM_176869.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76
• Publications: 0 publications found

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]

PPA2 Gene-Disease associations (from GenCC):

• sudden cardiac failure, infantile

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-105386625-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 372221.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24535418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPA2	NM_176869.3	c.881A>G	p.Gln294Arg	missense_variant	Exon 10 of 12	ENST00000341695.10	NP_789845.1
PPA2	NM_006903.4	c.794A>G	p.Gln265Arg	missense_variant	Exon 9 of 11		NP_008834.3
PPA2	NM_176866.2	c.575A>G	p.Gln192Arg	missense_variant	Exon 6 of 8		NP_789842.2
PPA2	NM_176867.3	c.383A>G	p.Gln128Arg	missense_variant	Exon 4 of 6		NP_789843.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPA2	ENST00000341695.10	c.881A>G	p.Gln294Arg	missense_variant	Exon 10 of 12	1	NM_176869.3	ENSP00000343885.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 294 of the PPA2 protein (p.Gln294Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PPA2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant disrupts the p.Gln294 amino acid residue in PPA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27523598). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T;.;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M;.;.;.
PhyloP100		2.8
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.94	N;N;N;N
REVEL	Benign	0.066
Sift	Uncertain	0.024	D;D;T;D
Sift4G	Benign	0.15	T;T;T;D
Vest4		0.45
ClinPred		0.67	D
GERP RS		5.0
Varity_R		0.10
gMVP		0.52
Mutation Taster		=83/17	polymorphism

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: rs1057517678; hg19: chr4-106307782;