4-105370525-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_176869.3(PPA2):c.976+312A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0995 in 851,284 control chromosomes in the GnomAD database, including 5,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1386 hom., cov: 32)
  • Exomes 𝑓: 0.098 (3664 hom.)
• Consequence: PPA2 NM_176869.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0130

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-105370525-T-C is Benign according to our data. Variant chr4-105370525-T-C is described in ClinVar as [Benign]. Clinvar id is 1289288.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPA2	NM_176869.3	c.976+312A>G		intron_variant		ENST00000341695.10
PPA2	NM_006903.4	c.889+312A>G		intron_variant
PPA2	NM_176866.2	c.670+312A>G		intron_variant
PPA2	NM_176867.3	c.478+312A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPA2	ENST00000341695.10	c.976+312A>G		intron_variant		1	NM_176869.3	P1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16273 AN: 151730 Hom.: 1384 Cov.: 32

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.111

GnomAD4 exome AF: 0.0978 AC: 68398 AN: 699436 Hom.: 3664 Cov.: 9 AF XY: 0.0975 AC XY: 31722 AN XY: 325494

Gnomad4 AFR exome AF: 0.0152

Gnomad4 AMR exome AF: 0.206

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.416

Gnomad4 SAS exome AF: 0.134

Gnomad4 FIN exome AF: 0.0973

Gnomad4 NFE exome AF: 0.0963

Gnomad4 OTH exome AF: 0.114

GnomAD4 genome AF: 0.107 AC: 16283 AN: 151848 Hom.: 1386 Cov.: 32 AF XY: 0.112 AC XY: 8284 AN XY: 74240

Gnomad4 AFR AF: 0.0241

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.430

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.113

Gnomad4 OTH AF: 0.118

Alfa AF: 0.0509 Hom.: 52

Bravo AF: 0.110

Asia WGS AF: 0.290 AC: 985 AN: 3400

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 11, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	3.6
Dann	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs35206705; hg19: chr4-106291682;