10-70213526-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_021129.4(PPA1):​c.448G>C​(p.Gly150Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PPA1
NM_021129.4 missense

Scores

12
5
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.89
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PPA1NM_021129.4 linkc.448G>C p.Gly150Arg missense_variant Exon 6 of 11 ENST00000373232.8 NP_066952.1 Q15181V9HWB5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PPA1ENST00000373232.8 linkc.448G>C p.Gly150Arg missense_variant Exon 6 of 11 1 NM_021129.4 ENSP00000362329.2 Q15181
PPA1ENST00000625364.1 linkc.448G>C p.Gly150Arg missense_variant Exon 6 of 7 5 ENSP00000486162.1 Q5SQT6
PPA1ENST00000373230.7 linkn.448G>C non_coding_transcript_exon_variant Exon 6 of 8 5 ENSP00000362327.4 Q5SQT6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251396
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461728
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
727166
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000468
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 15, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.448G>C (p.G150R) alteration is located in exon 6 (coding exon 6) of the PPA1 gene. This alteration results from a G to C substitution at nucleotide position 448, causing the glycine (G) at amino acid position 150 to be replaced by an arginine (R). 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
Pathogenic
0.73
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.80
D;T
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Benign
0.072
D
MetaRNN
Pathogenic
0.92
D;D
MetaSVM
Uncertain
0.31
D
MutationAssessor
Pathogenic
4.4
H;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-7.6
D;.
REVEL
Uncertain
0.51
Sift
Uncertain
0.0090
D;.
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;.
Vest4
0.80
MutPred
0.81
Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);
MVP
0.92
MPC
0.75
ClinPred
1.0
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.76
gMVP
0.91

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs1361336339; hg19: chr10-71973282; API