chr1-204406262-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate

The NM_032833.5(PPP1R15B):​c.1972C>T​(p.Arg658Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R658H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PPP1R15B
NM_032833.5 missense

Scores

8
6
2

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.58
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 Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-204406261-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 807902.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.97
PP5
Variant 1-204406262-G-A is Pathogenic according to our data. Variant chr1-204406262-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 222030.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PPP1R15BNM_032833.5 linkuse as main transcriptc.1972C>T p.Arg658Cys missense_variant 2/2 ENST00000367188.5
PPP1R15BXM_005245551.6 linkuse as main transcriptc.1920+3230C>T intron_variant
PPP1R15BXM_047432518.1 linkuse as main transcriptc.1920+3230C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PPP1R15BENST00000367188.5 linkuse as main transcriptc.1972C>T p.Arg658Cys missense_variant 2/21 NM_032833.5 P1
PPP1R15B-AS1ENST00000443515.1 linkuse as main transcriptn.146+28267G>A intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461804
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000151

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Microcephaly, short stature, and impaired glucose metabolism 2 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testing3billionMay 22, 2022The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26307080). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.68; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PPP1R15B- related disorder (ClinVar ID: VCV000222030 / PMID: 26307080). A different missense change at the same codon (p.Arg658His) has been reported to be associated with PPP1R15B- related disorder (ClinVar ID: VCV000807902). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 16, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
32
DANN
Pathogenic
1.0
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.93
D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Benign
-0.30
T
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-7.5
D
REVEL
Pathogenic
0.68
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0040
D
Vest4
0.71
MutPred
0.93
Loss of disorder (P = 0.0311);
MVP
0.76
MPC
0.57
ClinPred
1.0
D
GERP RS
4.6
gMVP
0.79

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: rs869025335; hg19: chr1-204375390; COSMIC: COSV65815650; API