4-105386625-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 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
• Publications: 3 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 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 VariationId is 372221.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPA2	NM_176869.3	c.881A>C	p.Gln294Pro	missense_variant	Exon 10 of 12	ENST00000341695.10	NP_789845.1
PPA2	NM_006903.4	c.794A>C	p.Gln265Pro	missense_variant	Exon 9 of 11		NP_008834.3
PPA2	NM_176866.2	c.575A>C	p.Gln192Pro	missense_variant	Exon 6 of 8		NP_789842.2
PPA2	NM_176867.3	c.383A>C	p.Gln128Pro	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>C	p.Gln294Pro	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: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Sudden cardiac failure, infantile Pathogenic:1

Nov 23, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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;.;.;.
PhyloP100		2.8
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
Vest4		0.90
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.41
gMVP		0.79
Mutation Taster		=0/100	disease causing (ClinVar)

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;