chr4-105369454-A-AC

Variant names:

• chr4-105369454-A-AC
• rs201046593
• NM_176869.3:c.*270dupG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_176869.3(PPA2):​c.*270dupG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 377,426 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0077 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: PPA2 NM_176869.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.460
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 4-105369454-A-AC is Benign according to our data. Variant chr4-105369454-A-AC is described in ClinVar as Likely_benign. ClinVar VariationId is 1213559.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00773 (1175/152006) while in subpopulation AFR AF = 0.0259 (1073/41360). AF 95% confidence interval is 0.0247. There are 20 homozygotes in GnomAd4. There are 574 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

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.*270dupG		3_prime_UTR	Exon 12 of 12	NP_789845.1	Q9H2U2-1
	PPA2	NM_006903.4		c.*270dupG		3_prime_UTR	Exon 11 of 11	NP_008834.3	Q9H2U2-3
	PPA2	NM_176866.2		c.*270dupG		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.*270dupG		3_prime_UTR	Exon 12 of 12	ENSP00000343885.5	Q9H2U2-1
	PPA2	ENST00000348706.9	TSL:1	c.*270dupG		3_prime_UTR	Exon 11 of 11	ENSP00000313061.8	Q9H2U2-3
	PPA2	ENST00000899797.1		c.*270dupG		3_prime_UTR	Exon 13 of 13	ENSP00000569856.1

Frequencies

GnomAD3 genomes AF: 0.00764 AC: 1160 AN: 151888 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00107 AC: 241 AN: 225420 Hom.: 1 Cov.: 0 AF XY: 0.00107 AC XY: 128 AN XY: 119876

African (AFR) AF: 0.0228 AC: 145 AN: 6370

American (AMR) AF: 0.00163 AC: 16 AN: 9810

Ashkenazi Jewish (ASJ) AF: 0.00220 AC: 15 AN: 6826

East Asian (EAS) AF: 0.00 AC: 0 AN: 13242

South Asian (SAS) AF: 0.0000841 AC: 2 AN: 23778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12336

Middle Eastern (MID) AF: 0.00191 AC: 2 AN: 1048

European-Non Finnish (NFE) AF: 0.000173 AC: 24 AN: 138824

Other (OTH) AF: 0.00281 AC: 37 AN: 13186

GnomAD4 genome AF: 0.00773 AC: 1175 AN: 152006 Hom.: 20 Cov.: 32 AF XY: 0.00772 AC XY: 574 AN XY: 74322

African (AFR) AF: 0.0259 AC: 1073 AN: 41360

American (AMR) AF: 0.00412 AC: 63 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67992

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00598 Hom.: 1

Bravo AF: 0.00855

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism

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: rs201046593; hg19: chr4-106290611;