rs772083375

Positions:

• chr4-105456721-G-A
• chr4-105456721-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_176869.3(PPA2):​c.182C>T​(p.Ser61Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,454,778 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S61P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PPA2 NM_176869.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.08

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 4-105456721-G-A is Pathogenic according to our data. Variant chr4-105456721-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372220.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPA2	NM_176869.3	c.182C>T	p.Ser61Phe	missense_variant	2/12	ENST00000341695.10
PPA2	NM_006903.4	c.182C>T	p.Ser61Phe	missense_variant	2/11
PPA2	NM_176866.2	c.182C>T	p.Ser61Phe	missense_variant	2/8
PPA2	NM_176867.3	c.157+17173C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPA2	ENST00000341695.10	c.182C>T	p.Ser61Phe	missense_variant	2/12	1	NM_176869.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000809 AC: 2 AN: 247094 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1454778 Hom.: 0 Cov.: 29 AF XY: 0.0000111 AC XY: 8 AN XY: 723916

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Sudden cardiac failure, infantile Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub	Sep 14, 2017	The c.182C>T variant is present in 2/242228 individuals in the gnomAD control population in heterozygous form, and has previously been reported in compound heterozygosity with another likely pathogenic PPA2 variant in four siblings with sudden infantile cardiac failure, showing autosomal recessive inheritance (Guimier et al (2016) Am J Hum Genet 99(3):666-673). In silico analysis predicts a pathogenic effect on protein function and the affected amino acid is highly conserved. Functional studies indicated that this variant adversely affects protein function (Guimier et al (2016)). The variant was detected in compound heterozygosity with another pathogenic variant in the proband, and in heterozygous form in an unaffected parent. In view of this evidence, we have interpreted this variant as likely to be pathogenic when inherited with another (likely) pathogenic variant. The variant is likely to be benign when carried in isolation. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 23, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;.;.;T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.7	M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;T;.
Polyphen		0.96	P;P;.;.;.
Vest4		0.98
MutPred		0.85		Gain of catalytic residue at S61 (P = 0.0822);Gain of catalytic residue at S61 (P = 0.0822);Gain of catalytic residue at S61 (P = 0.0822);Gain of catalytic residue at S61 (P = 0.0822);Gain of catalytic residue at S61 (P = 0.0822);
MVP		0.79
MPC		0.13
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.87
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs772083375; hg19: chr4-106377878; COSMIC: COSV58998878; COSMIC: COSV58998878;