Genetic Variant NM_015568.4:c.475G>C (chr20-38900588-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_015568.4(PPP1R16B):c.475G>C(p.Asp159His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. D159N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PPP1R16B
NM_015568.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.15

Publications

0 publications found

Variant links:

Genes affected

PPP1R16B (HGNC:15850): (protein phosphatase 1 regulatory subunit 16B) The protein encoded by this gene is membrane-associated and contains five ankyrin repeats, a protein phosphatase-1-interacting domain, and a carboxy-terminal CAAX box domain. Synthesis of the encoded protein is inhibited by transforming growth factor beta-1. The protein may bind to the membrane through its CAAX box domain and may act as a signaling molecule through interaction with protein phosphatase-1. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein. [provided by RefSeq, Sep 2015]

PPP1R16B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015568.4. 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
	PPP1R16B	NM_015568.4	MANE Select	c.475G>C	p.Asp159His	missense	Exon 5 of 11	NP_056383.1	Q96T49-1
	PPP1R16B	NM_001172735.3		c.475G>C	p.Asp159His	missense	Exon 5 of 10	NP_001166206.1	Q96T49-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPP1R16B	ENST00000299824.6	TSL:1 MANE Select	c.475G>C	p.Asp159His	missense	Exon 5 of 11	ENSP00000299824.1	Q96T49-1
PPP1R16B	ENST00000969166.1		c.475G>C	p.Asp159His	missense	Exon 5 of 11	ENSP00000639225.1
PPP1R16B	ENST00000969164.1		c.475G>C	p.Asp159His	missense	Exon 5 of 11	ENSP00000639223.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449686

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720648

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32908

American (AMR)

AF:

0.00

AC:

AN:

42888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25868

East Asian (EAS)

AF:

0.00

AC:

AN:

38682

South Asian (SAS)

AF:

0.00

AC:

AN:

83624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106790

Other (OTH)

AF:

0.00

AC:

AN:

59908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.020

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.1

PhyloP100

8.2

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.53

Sift

Benign

0.063

Sift4G

Benign

0.063

Polyphen

1.0

Vest4

0.92

MutPred

0.58

Gain of catalytic residue at L161 (P = 0.0763)

MVP

0.80

MPC

2.6

ClinPred

0.96

GERP RS

5.0

Varity_R

0.41

gMVP

0.81

Mutation Taster

=31/69

disease causing

(source)

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over