chr1-204409647-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_032833.5(PPP1R15B):ā€‹c.1765A>Gā€‹(p.Lys589Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,613,680 control chromosomes in the GnomAD database, including 467 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: š‘“ 0.015 ( 20 hom., cov: 32)
Exomes š‘“: 0.022 ( 447 hom. )

Consequence

PPP1R15B
NM_032833.5 missense

Scores

15

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.315
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 -14 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.002131939).
BP6
Variant 1-204409647-T-C is Benign according to our data. Variant chr1-204409647-T-C is described in ClinVar as [Benign]. Clinvar id is 2039413.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0153 (2333/152212) while in subpopulation SAS AF= 0.0381 (184/4824). AF 95% confidence interval is 0.0336. There are 20 homozygotes in gnomad4. There are 1146 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PPP1R15BNM_032833.5 linkuse as main transcriptc.1765A>G p.Lys589Glu missense_variant 1/2 ENST00000367188.5
PPP1R15BXM_005245551.6 linkuse as main transcriptc.1765A>G p.Lys589Glu missense_variant 1/3
PPP1R15BXM_047432518.1 linkuse as main transcriptc.1765A>G p.Lys589Glu missense_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PPP1R15BENST00000367188.5 linkuse as main transcriptc.1765A>G p.Lys589Glu missense_variant 1/21 NM_032833.5 P1
PPP1R15B-AS1ENST00000443515.1 linkuse as main transcriptn.147-25690T>C intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0153
AC:
2334
AN:
152094
Hom.:
20
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00398
Gnomad AMI
AF:
0.00219
Gnomad AMR
AF:
0.0130
Gnomad ASJ
AF:
0.0286
Gnomad EAS
AF:
0.000962
Gnomad SAS
AF:
0.0379
Gnomad FIN
AF:
0.0123
Gnomad MID
AF:
0.0380
Gnomad NFE
AF:
0.0222
Gnomad OTH
AF:
0.0153
GnomAD3 exomes
AF:
0.0192
AC:
4839
AN:
251472
Hom.:
84
AF XY:
0.0214
AC XY:
2908
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.00289
Gnomad AMR exome
AF:
0.0105
Gnomad ASJ exome
AF:
0.0327
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.0454
Gnomad FIN exome
AF:
0.0114
Gnomad NFE exome
AF:
0.0205
Gnomad OTH exome
AF:
0.0199
GnomAD4 exome
AF:
0.0219
AC:
31938
AN:
1461468
Hom.:
447
Cov.:
32
AF XY:
0.0228
AC XY:
16595
AN XY:
727054
show subpopulations
Gnomad4 AFR exome
AF:
0.00314
Gnomad4 AMR exome
AF:
0.0102
Gnomad4 ASJ exome
AF:
0.0311
Gnomad4 EAS exome
AF:
0.000202
Gnomad4 SAS exome
AF:
0.0435
Gnomad4 FIN exome
AF:
0.0113
Gnomad4 NFE exome
AF:
0.0222
Gnomad4 OTH exome
AF:
0.0225
GnomAD4 genome
AF:
0.0153
AC:
2333
AN:
152212
Hom.:
20
Cov.:
32
AF XY:
0.0154
AC XY:
1146
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.00397
Gnomad4 AMR
AF:
0.0129
Gnomad4 ASJ
AF:
0.0286
Gnomad4 EAS
AF:
0.000964
Gnomad4 SAS
AF:
0.0381
Gnomad4 FIN
AF:
0.0123
Gnomad4 NFE
AF:
0.0222
Gnomad4 OTH
AF:
0.0152
Alfa
AF:
0.0214
Hom.:
59
Bravo
AF:
0.0140
TwinsUK
AF:
0.0208
AC:
77
ALSPAC
AF:
0.0218
AC:
84
ESP6500AA
AF:
0.00590
AC:
26
ESP6500EA
AF:
0.0235
AC:
202
ExAC
AF:
0.0189
AC:
2290
Asia WGS
AF:
0.0150
AC:
51
AN:
3478
EpiCase
AF:
0.0216
EpiControl
AF:
0.0223

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.74
T
BayesDel_noAF
Benign
-0.81
CADD
Benign
0.84
DANN
Benign
0.54
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.070
N
MetaRNN
Benign
0.0021
T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-0.050
N
REVEL
Benign
0.0090
Sift
Benign
0.55
T
Sift4G
Benign
1.0
T
Vest4
0.016
MPC
0.13
ClinPred
0.00030
T
GERP RS
-1.3
gMVP
0.12

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: rs17855962; hg19: chr1-204378775; API