4-105369737-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_176869.3(PPA2):c.993C>G(p.Phe331Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. F331C) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: PPA2 NM_176869.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35539356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPA2	NM_176869.3	c.993C>G	p.Phe331Leu	missense_variant	12/12	ENST00000341695.10
PPA2	NM_006903.4	c.906C>G	p.Phe302Leu	missense_variant	11/11
PPA2	NM_176866.2	c.687C>G	p.Phe229Leu	missense_variant	8/8
PPA2	NM_176867.3	c.495C>G	p.Phe165Leu	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPA2	ENST00000341695.10	c.993C>G	p.Phe331Leu	missense_variant	12/12	1	NM_176869.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74272

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 14, 2022

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 331 of the PPA2 protein (p.Phe331Leu). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.66	T;T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.4	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.46
MutPred		0.50		Loss of glycosylation at K334 (P = 0.0753);.;.;.;
MVP		0.55
MPC		0.51
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs939247653; hg19: chr4-106290894;