Genetic Variant PPA1:p.Glu209Lys (chr10-70209572-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_021129.4(PPA1):c.625G>A(p.Glu209Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000172 in 1,601,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

PPA1
NM_021129.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.93

Variant links:

Genes affected

PPA1 (HGNC:9226): (inorganic pyrophosphatase 1) The protein encoded by this gene is a member of the inorganic pyrophosphatase (PPase) family. PPases catalyze the hydrolysis of pyrophosphate to inorganic phosphate, which is important for the phosphate metabolism of cells. Studies of a similar protein in bovine suggested a cytoplasmic localization of this enzyme. [provided by RefSeq, Jul 2008]

PPA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29260683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPA1	NM_021129.4 link	c.625G>A	p.Glu209Lys	missense_variant	Exon 7 of 11	ENST00000373232.8	NP_066952.1	Q15181V9HWB5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PPA1	ENST00000373232.8 link	c.625G>A	p.Glu209Lys	missense_variant	Exon 7 of 11	1	NM_021129.4	ENSP00000362329.2	Q15181
PPA1	ENST00000610026.1 link	n.679G>A		non_coding_transcript_exon_variant	Exon 1 of 3	2
PPA1	ENST00000373230.7 link	n.*313G>A		downstream_gene_variant		5		ENSP00000362327.4	Q5SQT6

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

239874

Hom.:

AF XY:

0.0000695

AC XY:

AN XY:

129586

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000171

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000181

AC:

263

AN:

1449724

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

118

AN XY:

720904

show subpopulations

Gnomad4 AFR exome

AF:

0.0000306

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000232

Gnomad4 OTH exome

AF:

0.0000835

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.625G>A (p.E209K) alteration is located in exon 7 (coding exon 7) of the PPA1 gene. This alteration results from a G to A substitution at nucleotide position 625, causing the glutamic acid (E) at amino acid position 209 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Benign

0.027

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.015

MetaRNN

Benign

0.29

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.063

Sift

Benign

0.081

Sift4G

Benign

0.38

Polyphen

0.011

Vest4

0.46

MVP

0.82

MPC

0.20

ClinPred

0.14

GERP RS

4.4

Varity_R

0.59

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over