chr1-204409526-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032833.5(PPP1R15B):ā€‹c.1886C>Gā€‹(p.Ser629Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000826 in 1,613,160 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0041 ( 7 hom., cov: 32)
Exomes š‘“: 0.00048 ( 9 hom. )

Consequence

PPP1R15B
NM_032833.5 missense

Scores

5
10

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.410
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-AS1 (HGNC:55838): (PPP1R15B and PIK3C2B antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.007181585).
BP6
Variant 1-204409526-G-C is Benign according to our data. Variant chr1-204409526-G-C is described in ClinVar as [Benign]. Clinvar id is 716902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-204409526-G-C is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000481 (703/1460892) while in subpopulation AFR AF= 0.0164 (548/33428). AF 95% confidence interval is 0.0153. There are 9 homozygotes in gnomad4_exome. There are 277 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PPP1R15BNM_032833.5 linkuse as main transcriptc.1886C>G p.Ser629Cys missense_variant 1/2 ENST00000367188.5
PPP1R15BXM_005245551.6 linkuse as main transcriptc.1886C>G p.Ser629Cys missense_variant 1/3
PPP1R15BXM_047432518.1 linkuse as main transcriptc.1886C>G p.Ser629Cys missense_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PPP1R15BENST00000367188.5 linkuse as main transcriptc.1886C>G p.Ser629Cys missense_variant 1/21 NM_032833.5 P1
PPP1R15B-AS1ENST00000443515.1 linkuse as main transcriptn.147-25811G>C intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00413
AC:
628
AN:
152150
Hom.:
7
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0140
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00242
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.00108
AC:
271
AN:
250202
Hom.:
0
AF XY:
0.000688
AC XY:
93
AN XY:
135224
show subpopulations
Gnomad AFR exome
AF:
0.0142
Gnomad AMR exome
AF:
0.000933
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000354
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000481
AC:
703
AN:
1460892
Hom.:
9
Cov.:
32
AF XY:
0.000381
AC XY:
277
AN XY:
726686
show subpopulations
Gnomad4 AFR exome
AF:
0.0164
Gnomad4 AMR exome
AF:
0.000943
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000105
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000252
Gnomad4 OTH exome
AF:
0.00121
GnomAD4 genome
AF:
0.00413
AC:
629
AN:
152268
Hom.:
7
Cov.:
32
AF XY:
0.00419
AC XY:
312
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.0140
Gnomad4 AMR
AF:
0.00242
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.000362
Hom.:
0
Bravo
AF:
0.00455
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.0118
AC:
52
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00123
AC:
149
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2023PPP1R15B: BP4, BS1, BS2 -
Benign, criteria provided, single submitterclinical testingInvitaeJan 23, 2024- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 06, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.60
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
20
DANN
Uncertain
0.98
Eigen
Benign
-0.12
Eigen_PC
Benign
-0.065
FATHMM_MKL
Uncertain
0.87
D
MetaRNN
Benign
0.0072
T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
0.93
N
PrimateAI
Benign
0.33
T
PROVEAN
Uncertain
-2.7
D
REVEL
Benign
0.081
Sift
Uncertain
0.019
D
Sift4G
Uncertain
0.0080
D
Vest4
0.12
MVP
0.48
MPC
0.25
ClinPred
0.028
T
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.39

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: rs111725786; hg19: chr1-204378654; COSMIC: COSV99057185; API