chr4-105370521-GT-G

Variant names:

• chr4-105370521-GT-G
• rs147156921
• NM_176869.3:c.976+315delA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_176869.3(PPA2):​c.976+315delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 798,336 control chromosomes in the GnomAD database, including 546 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.040 (399 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (147 hom.)
• Consequence: PPA2 NM_176869.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0620
• 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: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 4-105370521-GT-G is Benign according to our data. Variant chr4-105370521-GT-G is described in ClinVar as Benign. ClinVar VariationId is 1177827.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 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.976+315delA		intron	N/A	NP_789845.1	Q9H2U2-1
	PPA2	NM_006903.4		c.889+315delA		intron	N/A	NP_008834.3	Q9H2U2-3
	PPA2	NM_176866.2		c.670+315delA		intron	N/A	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.976+315delA		intron	N/A	ENSP00000343885.5	Q9H2U2-1
	PPA2	ENST00000348706.9	TSL:1	c.889+315delA		intron	N/A	ENSP00000313061.8	Q9H2U2-3
	PPA2	ENST00000432483.6	TSL:1	c.670+315delA		intron	N/A	ENSP00000389957.2	Q9H2U2-6

Frequencies

GnomAD3 genomes AF: 0.0400 AC: 5996 AN: 149966 Hom.: 399 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000838

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000519

Gnomad OTH AF: 0.0279

GnomAD4 exome AF: 0.00336 AC: 2180 AN: 648258 Hom.: 147 Cov.: 7 AF XY: 0.00317 AC XY: 957 AN XY: 302078

African (AFR) AF: 0.151 AC: 1824 AN: 12108

American (AMR) AF: 0.00706 AC: 5 AN: 708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4068

East Asian (EAS) AF: 0.00 AC: 0 AN: 2650

South Asian (SAS) AF: 0.000320 AC: 4 AN: 12508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 218

Middle Eastern (MID) AF: 0.00719 AC: 9 AN: 1252

European-Non Finnish (NFE) AF: 0.000301 AC: 179 AN: 593734

Other (OTH) AF: 0.00757 AC: 159 AN: 21012

GnomAD4 genome AF: 0.0400 AC: 6001 AN: 150078 Hom.: 399 Cov.: 32 AF XY: 0.0385 AC XY: 2820 AN XY: 73288

African (AFR) AF: 0.138 AC: 5655 AN: 40888

American (AMR) AF: 0.0164 AC: 248 AN: 15100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000840 AC: 4 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9974

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000519 AC: 35 AN: 67448

Other (OTH) AF: 0.0276 AC: 58 AN: 2102

Alfa AF: 0.00120 Hom.: 0

Bravo AF: 0.0463

Asia WGS AF: 0.00707 AC: 24 AN: 3410

ClinVar

ClinVar submissions

Significance: 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		-0.062
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: rs147156921; hg19: chr4-106291678;