4-105369600-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_176869.3(PPA2):c.*125C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 810,672 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (15 hom., cov: 32)
  • Exomes 𝑓: 0.014 (105 hom.)
• Consequence: PPA2 NM_176869.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0860

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=-0.84).
• BP6: Variant 4-105369600-G-A is Benign according to our data. Variant chr4-105369600-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1194162.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0104 (1575/152168) while in subpopulation NFE AF= 0.0177 (1204/68004). AF 95% confidence interval is 0.0169. There are 15 homozygotes in gnomad4. There are 707 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPA2	NM_176869.3	c.*125C>T		3_prime_UTR_variant	12/12	ENST00000341695.10
PPA2	NM_006903.4	c.*125C>T		3_prime_UTR_variant	11/11
PPA2	NM_176866.2	c.*125C>T		3_prime_UTR_variant	8/8
PPA2	NM_176867.3	c.*125C>T		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPA2	ENST00000341695.10	c.*125C>T		3_prime_UTR_variant	12/12	1	NM_176869.3	P1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1575 AN: 152050 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00871

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00624

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.00814

GnomAD4 exome AF: 0.0140 AC: 9226 AN: 658504 Hom.: 105 Cov.: 9 AF XY: 0.0136 AC XY: 4768 AN XY: 350312

Gnomad4 AFR exome AF: 0.00342

Gnomad4 AMR exome AF: 0.00881

Gnomad4 ASJ exome AF: 0.00404

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00178

Gnomad4 FIN exome AF: 0.00629

Gnomad4 NFE exome AF: 0.0191

Gnomad4 OTH exome AF: 0.0131

GnomAD4 genome AF: 0.0104 AC: 1575 AN: 152168 Hom.: 15 Cov.: 32 AF XY: 0.00950 AC XY: 707 AN XY: 74392

Gnomad4 AFR AF: 0.00311

Gnomad4 AMR AF: 0.00870

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00624

Gnomad4 NFE AF: 0.0177

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.0128 Hom.: 4

Bravo AF: 0.0106

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 22, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.93
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: rs148302883; hg19: chr4-106290757;