Genetic Variant NM_021129.4:c.-11A>C (chr10-70233338-T-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021129.4(PPA1):c.-11A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,534,116 control chromosomes in the GnomAD database, including 73,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5582 hom., cov: 33)

Exomes 𝑓: 0.31 ( 68212 hom. )

Consequence

PPA1
NM_021129.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.334

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 10-70233338-T-G is Benign according to our data. Variant chr10-70233338-T-G is described in ClinVar as [Benign]. Clinvar id is 403335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPA1	NM_021129.4 link	c.-11A>C		5_prime_UTR_variant	Exon 1 of 11	ENST00000373232.8	NP_066952.1	Q15181V9HWB5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PPA1	ENST00000373232.8 link	c.-11A>C	5_prime_UTR_variant	Exon 1 of 11	1	NM_021129.4	ENSP00000362329.2	Q15181
PPA1	ENST00000625364.1 link	c.-11A>C	5_prime_UTR_variant	Exon 1 of 7	5		ENSP00000486162.1	Q5SQT6
PPA1	ENST00000495346.1 link	n.184+390A>C	intron_variant	Intron 1 of 2	3
PPA1	ENST00000373230.7 link	n.-11A>C	upstream_gene_variant		5		ENSP00000362327.4	Q5SQT6

Frequencies

GnomAD3 genomes

AF:

0.245

AC:

37207

AN:

151916

Hom.:

5581

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0999

Gnomad AMI

AF:

0.281

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.243

Gnomad EAS

AF:

0.0363

Gnomad SAS

AF:

0.283

Gnomad FIN

AF:

0.406

Gnomad MID

AF:

0.290

Gnomad NFE

AF:

0.328

Gnomad OTH

AF:

0.258

GnomAD3 exomes

AF:

0.258

AC:

33528

AN:

129942

Hom.:

5026

AF XY:

0.265

AC XY:

18662

AN XY:

70340

show subpopulations

Gnomad AFR exome

AF:

0.0895

Gnomad AMR exome

AF:

0.171

Gnomad ASJ exome

AF:

0.240

Gnomad EAS exome

AF:

0.0357

Gnomad SAS exome

AF:

0.280

Gnomad FIN exome

AF:

0.399

Gnomad NFE exome

AF:

0.321

Gnomad OTH exome

AF:

0.266

GnomAD4 exome

AF:

0.307

AC:

423707

AN:

1382088

Hom.:

68212

Cov.:

AF XY:

0.306

AC XY:

208271

AN XY:

681672

show subpopulations

Gnomad4 AFR exome

AF:

0.0898

Gnomad4 AMR exome

AF:

0.184

Gnomad4 ASJ exome

AF:

0.237

Gnomad4 EAS exome

AF:

0.0300

Gnomad4 SAS exome

AF:

0.285

Gnomad4 FIN exome

AF:

0.398

Gnomad4 NFE exome

AF:

0.326

Gnomad4 OTH exome

AF:

0.282

GnomAD4 genome

AF:

0.245

AC:

37204

AN:

152028

Hom.:

5582

Cov.:

AF XY:

0.248

AC XY:

18456

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0998

Gnomad4 AMR

AF:

0.210

Gnomad4 ASJ

AF:

0.243

Gnomad4 EAS

AF:

0.0364

Gnomad4 SAS

AF:

0.284

Gnomad4 FIN

AF:

0.406

Gnomad4 NFE

AF:

0.328

Gnomad4 OTH

AF:

0.255

Alfa

AF:

0.281

Hom.:

1228

Bravo

AF:

0.220

Asia WGS

AF:

0.153

AC:

534

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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.

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