rs1057517680

Positions:

• chr4-105449353-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_176869.3(PPA2):​c.318G>T​(p.Met106Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000709 in 1,409,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: PPA2 NM_176869.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.60

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751
• PP5: Variant 4-105449353-C-A is Pathogenic according to our data. Variant chr4-105449353-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 372224.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.318G>T	p.Met106Ile	missense_variant	4/12	ENST00000341695.10
PPA2	NM_006903.4	c.318G>T	p.Met106Ile	missense_variant	4/11
PPA2	NM_176866.2	c.222+7328G>T		intron_variant
PPA2	NM_176867.3	c.157+24541G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPA2	ENST00000341695.10	c.318G>T	p.Met106Ile	missense_variant	4/12	1	NM_176869.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000709 AC: 10 AN: 1409588 Hom.: 0 Cov.: 27 AF XY: 0.00000853 AC XY: 6 AN XY: 703608

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000840

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 31

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	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Pathogenic	3.0	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.016	D;D;D;D
Sift4G	Uncertain	0.045	D;D;.;T
Polyphen		0.93	P;B;.;.
Vest4		0.92
MutPred		0.64		Gain of methylation at K105 (P = 0.0391);Gain of methylation at K105 (P = 0.0391);.;.;
MVP		0.55
MPC		0.52
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.67
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1057517680; hg19: chr4-106370510;