chr1-204409647-T-C

Position:

• chr1-204409647-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_032833.5(PPP1R15B):​c.1765A>G​(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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.015 (20 hom., cov: 32)
  • Exomes 𝑓: 0.022 (447 hom.)
• Consequence: PPP1R15B NM_032833.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.315

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)

ACMG classification

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
PPP1R15B	NM_032833.5	c.1765A>G	p.Lys589Glu	missense_variant	1/2	ENST00000367188.5
PPP1R15B	XM_005245551.6	c.1765A>G	p.Lys589Glu	missense_variant	1/3
PPP1R15B	XM_047432518.1	c.1765A>G	p.Lys589Glu	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1R15B	ENST00000367188.5	c.1765A>G	p.Lys589Glu	missense_variant	1/2	1	NM_032833.5	P1
PPP1R15B-AS1	ENST00000443515.1	n.147-25690T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2334 AN: 152094 Hom.: 20 Cov.: 32

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

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

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

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

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 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

Other links and lift over

dbSNP: rs17855962; hg19: chr1-204378775;