Genetic Variant NM_002652.3:c.98G>A (chr7-143135196-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002652.3(PIP):c.98G>A(p.Arg33Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000189 in 1,531,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R33L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

PIP
NM_002652.3 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0130

Publications

0 publications found

Variant links:

Genes affected

PIP (HGNC:8993): (prolactin induced protein) Enables IgG binding activity; aspartic-type endopeptidase activity; and identical protein binding activity. Involved in several processes, including detection of chemical stimulus involved in sensory perception of bitter taste; negative regulation of T cell apoptotic process; and proteolysis. Located in extracellular space and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

PIP links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09019151).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002652.3. 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
	PIP	NM_002652.3	MANE Select	c.98G>A	p.Arg33Gln	missense splice_region	Exon 2 of 4	NP_002643.1	P12273

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIP	ENST00000291009.4	TSL:1 MANE Select	c.98G>A	p.Arg33Gln	missense splice_region	Exon 2 of 4	ENSP00000291009.3	P12273

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151942

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000726

AC:

AN:

247808

AF XY:

0.0000672

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000438

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000174

AC:

AN:

1379958

Hom.:

Cov.:

AF XY:

0.0000188

AC XY:

AN XY:

690420

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31998

American (AMR)

AF:

0.000157

AC:

AN:

44508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25354

East Asian (EAS)

AF:

0.000102

AC:

AN:

39240

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84298

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

0.00000771

AC:

AN:

1038242

Other (OTH)

AF:

0.0000695

AC:

AN:

57570

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151942

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74196

show subpopulations

African (AFR)

AF:

0.0000967

AC:

AN:

41386

American (AMR)

AF:

0.0000656

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67952

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000550

EpiControl

AF:

0.0000598

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.094

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.62

M_CAP

Benign

0.0041

MetaRNN

Benign

0.090

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

-0.013

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.48

REVEL

Benign

0.099

Sift

Benign

0.13

Sift4G

Benign

0.31

Polyphen

0.99

Vest4

0.11

MVP

0.17

MPC

0.095

ClinPred

0.025

GERP RS

-1.2

Varity_R

0.16

gMVP

0.18

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over