chr1-204406262-G-A

Variant names:

• chr1-204406262-G-A
• rs869025335
• NM_032833.5:c.1972C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM2 PM5 PP3_Strong PP5

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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002521176: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:26307080).". 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.58
• Publications: 11 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: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002521176: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26307080).
• 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 VariationId is 807902.
• 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 222030.

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.1972C>T	p.Arg658Cys	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.1972C>T	p.Arg658Cys	missense	Exon 2 of 2	ENSP00000356156.4	Q5SWA1
	PPP1R15B	ENST00000693720.1		c.1920+3230C>T		intron	N/A	ENSP00000508814.1	A0A8I5KSH1
	PPP1R15B	ENST00000689921.1		n.*119C>T		non_coding_transcript_exon	Exon 3 of 3	ENSP00000510434.1	A0A8I5KUJ3

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Microcephaly, short stature, and impaired glucose metabolism 2 (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.6
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
Mutation Taster		=33/67	disease causing (ClinVar)

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

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