rs16345

Variant names:

• chr4-105369672-A-ACTTGGGGAAAAAGAGT
• rs16345
• NM_176869.3:c.*52_*53insACTCTTTTTCCCCAAG

Your query was ambiguous. Multiple possible variants found:

• chr4-105369672-A-ACTTGGGGAAAAAGAGT
• chr4-105369672-A-ACTTGG
• chr4-105369672-A-ACTTGGGAAAAAAGAGT
• chr4-105369672-A-ACTTGGGGAAAAACAGT
• chr4-105369672-A-ACTTGGGGAAAAAGT

Variant summary

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

The NM_176869.3(PPA2):​c.*52_*53insACTCTTTTTCCCCAAG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,492,210 control chromosomes in the GnomAD database, including 59,685 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.33 (8501 hom., cov: 0)
  • Exomes 𝑓: 0.27 (51184 hom.)
• Consequence: PPA2 NM_176869.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.560
• Publications: 6 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 4-105369672-A-ACTTGGGGAAAAAGAGT is Benign according to our data. Variant chr4-105369672-A-ACTTGGGGAAAAAGAGT is described in ClinVar as Benign. ClinVar VariationId is 1269365.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.43 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.*52_*53insACTCTTTTTCCCCAAG		3_prime_UTR	Exon 12 of 12	NP_789845.1	Q9H2U2-1
	PPA2	NM_006903.4		c.*52_*53insACTCTTTTTCCCCAAG		3_prime_UTR	Exon 11 of 11	NP_008834.3	Q9H2U2-3
	PPA2	NM_176866.2		c.*52_*53insACTCTTTTTCCCCAAG		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.*52_*53insACTCTTTTTCCCCAAG		3_prime_UTR	Exon 12 of 12	ENSP00000343885.5	Q9H2U2-1
	PPA2	ENST00000348706.9	TSL:1	c.*52_*53insACTCTTTTTCCCCAAG		3_prime_UTR	Exon 11 of 11	ENSP00000313061.8	Q9H2U2-3
	PPA2	ENST00000432483.6	TSL:1	c.*52_*53insACTCTTTTTCCCCAAG		3_prime_UTR	Exon 8 of 8	ENSP00000389957.2	Q9H2U2-6

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49305 AN: 151770 Hom.: 8481 Cov.: 0

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.317

GnomAD4 exome AF: 0.270 AC: 362369 AN: 1340322 Hom.: 51184 Cov.: 27 AF XY: 0.269 AC XY: 180552 AN XY: 672354

African (AFR) AF: 0.439 AC: 13372 AN: 30456

American (AMR) AF: 0.339 AC: 15065 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 7058 AN: 25376

East Asian (EAS) AF: 0.456 AC: 17754 AN: 38936

South Asian (SAS) AF: 0.236 AC: 19744 AN: 83640

European-Finnish (FIN) AF: 0.241 AC: 12758 AN: 53020

Middle Eastern (MID) AF: 0.261 AC: 1451 AN: 5554

European-Non Finnish (NFE) AF: 0.258 AC: 259015 AN: 1002526

Other (OTH) AF: 0.286 AC: 16152 AN: 56382

GnomAD4 genome AF: 0.325 AC: 49380 AN: 151888 Hom.: 8501 Cov.: 0 AF XY: 0.324 AC XY: 24026 AN XY: 74230

African (AFR) AF: 0.435 AC: 17991 AN: 41350

American (AMR) AF: 0.332 AC: 5061 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1017 AN: 3472

East Asian (EAS) AF: 0.434 AC: 2238 AN: 5156

South Asian (SAS) AF: 0.240 AC: 1150 AN: 4800

European-Finnish (FIN) AF: 0.243 AC: 2573 AN: 10580

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18359 AN: 67952

Other (OTH) AF: 0.321 AC: 676 AN: 2108

Alfa AF: 0.130 Hom.: 180

Asia WGS AF: 0.368 AC: 1283 AN: 3478

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		-0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16345; hg19: chr4-106290829; COSMIC: COSV58993195;