NM_032833.5:c.1969G>A

Variant names:

• chr1-204406265-C-T
• NM_032833.5:c.1969G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_032833.5(PPP1R15B):​c.1969G>A​(p.Asp657Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP1R15B NM_032833.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_032833.5
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032833.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R15B	NM_032833.5	MANE Select	c.1969G>A	p.Asp657Asn	missense	Exon 2 of 2	NP_116222.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R15B	ENST00000367188.5	TSL:1 MANE Select	c.1969G>A	p.Asp657Asn	missense	Exon 2 of 2	ENSP00000356156.4	Q5SWA1
	PPP1R15B	ENST00000693720.1		c.1920+3227G>A		intron	N/A	ENSP00000508814.1	A0A8I5KSH1
	PPP1R15B	ENST00000689921.1		n.*116G>A		non_coding_transcript_exon	Exon 3 of 3	ENSP00000510434.1	A0A8I5KUJ3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.83	T
PhyloP100		5.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.24
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.049	D
Vest4		0.38
MutPred		0.71		Gain of methylation at K659 (P = 0.0726)
MVP		0.70
MPC		0.49
ClinPred		0.92	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.50
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

hg19: chr1-204375393;