chr1-204409718-G-A

Position:

chr1-204409718-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000367188.5(PPP1R15B):c.1694C>T(p.Pro565Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000145 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

PPP1R15B
ENST00000367188.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.72

Variant links:

Genes affected

PPP1R15B (HGNC:14951): (protein phosphatase 1 regulatory subunit 15B) This gene encodes a protein phosphatase I-interacting protein that promotes the dephosphorylation of eukaryotic translation initiation factor 2A to regulate translation under conditions of cellular stress. The transcribed messenger RNA contains two upstream open reading frames (ORFs) that repress translation of the main protein coding ORF under normal conditions, while the protein coding ORF is expressed at high levels in response to stress. Continual translation of the mRNA under conditions of eukaryotic translation initiation factor 2A inactivation is thought to create a feedback loop for reactivation of the gene during recovery from stress. In addition, it has been shown that this protein plays a role in membrane traffic that is independent of translation and that it is required for exocytosis from erythroleukemia cells. Allelic variants of this gene are associated with microcephaly, short stature, and impaired glucose metabolism. [provided by RefSeq, Feb 2016]

PPP1R15B links:

PPP1R15B-AS1 (HGNC:55838): (PPP1R15B and PIK3C2B antisense RNA 1)

PPP1R15B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PPP1R15B	NM_032833.5 linkuse as main transcript	c.1694C>T	p.Pro565Leu	missense_variant	1/2	ENST00000367188.5	NP_116222.4
PPP1R15B	XM_005245551.6 linkuse as main transcript	c.1694C>T	p.Pro565Leu	missense_variant	1/3		XP_005245608.2
PPP1R15B	XM_047432518.1 linkuse as main transcript	c.1694C>T	p.Pro565Leu	missense_variant	1/3		XP_047288474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1R15B	ENST00000367188.5 linkuse as main transcript	c.1694C>T	p.Pro565Leu	missense_variant	1/2	1	NM_032833.5	ENSP00000356156	P1
PPP1R15B-AS1	ENST00000443515.1 linkuse as main transcript	n.147-25619G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

251362

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000146

AC:

214

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

118

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.000918

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000155

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000132

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000232

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 01, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 30, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 565 of the PPP1R15B protein (p.Pro565Leu). This variant is present in population databases (rs147451458, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PPP1R15B-related conditions. ClinVar contains an entry for this variant (Variation ID: 436407). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.052

MetaRNN

Uncertain

0.50

MetaSVM

Uncertain

-0.26

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.3

REVEL

Uncertain

0.50

Sift

Benign

0.056

Sift4G

Uncertain

0.056

Vest4

0.60

MVP

0.84

MPC

0.49

ClinPred

0.82

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.57

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