rs112734002

Variant names:

• chr4-105369463-T-C
• rs112734002
• NM_176869.3:c.*262A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_176869.3(PPA2):​c.*262A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 397,326 control chromosomes in the GnomAD database, including 2,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1201 hom., cov: 32)
  • Exomes 𝑓: 0.10 (1582 hom.)
• Consequence: PPA2 NM_176869.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.401
• 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), Laboratory for Molecular Medicine, Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 4-105369463-T-C is Benign according to our data. Variant chr4-105369463-T-C is described in ClinVar as Benign. ClinVar VariationId is 1182538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176869.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPA2	NM_176869.3	MANE Select	c.*262A>G		3_prime_UTR	Exon 12 of 12	NP_789845.1	Q9H2U2-1
	PPA2	NM_006903.4		c.*262A>G		3_prime_UTR	Exon 11 of 11	NP_008834.3	Q9H2U2-3
	PPA2	NM_176866.2		c.*262A>G		3_prime_UTR	Exon 8 of 8	NP_789842.2	Q9H2U2-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPA2	ENST00000341695.10	TSL:1 MANE Select	c.*262A>G		3_prime_UTR	Exon 12 of 12	ENSP00000343885.5	Q9H2U2-1
	PPA2	ENST00000348706.9	TSL:1	c.*262A>G		3_prime_UTR	Exon 11 of 11	ENSP00000313061.8	Q9H2U2-3
	PPA2	ENST00000899797.1		c.*262A>G		3_prime_UTR	Exon 13 of 13	ENSP00000569856.1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18630 AN: 151994 Hom.: 1200 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0898

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.0686

Gnomad FIN AF: 0.0934

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.130

GnomAD4 exome AF: 0.104 AC: 25410 AN: 245214 Hom.: 1582 Cov.: 0 AF XY: 0.101 AC XY: 13108 AN XY: 130314

African (AFR) AF: 0.144 AC: 996 AN: 6910

American (AMR) AF: 0.0903 AC: 965 AN: 10686

Ashkenazi Jewish (ASJ) AF: 0.0811 AC: 603 AN: 7434

East Asian (EAS) AF: 0.00381 AC: 57 AN: 14948

South Asian (SAS) AF: 0.0607 AC: 1571 AN: 25886

European-Finnish (FIN) AF: 0.0930 AC: 1273 AN: 13686

Middle Eastern (MID) AF: 0.0813 AC: 93 AN: 1144

European-Non Finnish (NFE) AF: 0.122 AC: 18253 AN: 150112

Other (OTH) AF: 0.111 AC: 1599 AN: 14408

GnomAD4 genome AF: 0.123 AC: 18642 AN: 152112 Hom.: 1201 Cov.: 32 AF XY: 0.119 AC XY: 8826 AN XY: 74370

African (AFR) AF: 0.148 AC: 6131 AN: 41480

American (AMR) AF: 0.106 AC: 1617 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0898 AC: 311 AN: 3464

East Asian (EAS) AF: 0.00502 AC: 26 AN: 5180

South Asian (SAS) AF: 0.0686 AC: 331 AN: 4822

European-Finnish (FIN) AF: 0.0934 AC: 987 AN: 10572

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8795 AN: 68000

Other (OTH) AF: 0.127 AC: 269 AN: 2112

Alfa AF: 0.132 Hom.: 164

Bravo AF: 0.124

Asia WGS AF: 0.0510 AC: 180 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.16
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs112734002; hg19: chr4-106290620;