chr20-38900588-G-A

Variant names:

• chr20-38900588-G-A
• rs866362326
• NM_015568.4:c.475G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_015568.4(PPP1R16B):​c.475G>A​(p.Asp159Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,449,686 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PPP1R16B NM_015568.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.15
• Publications: 1 publications found

Genes affected

PPP1R16B (HGNC:15850): (protein phosphatase 1 regulatory subunit 16B) The protein encoded by this gene is membrane-associated and contains five ankyrin repeats, a protein phosphatase-1-interacting domain, and a carboxy-terminal CAAX box domain. Synthesis of the encoded protein is inhibited by transforming growth factor beta-1. The protein may bind to the membrane through its CAAX box domain and may act as a signaling molecule through interaction with protein phosphatase-1. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein. [provided by RefSeq, Sep 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015568.4. 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
	PPP1R16B	NM_015568.4	MANE Select	c.475G>A	p.Asp159Asn	missense	Exon 5 of 11	NP_056383.1	Q96T49-1
	PPP1R16B	NM_001172735.3		c.475G>A	p.Asp159Asn	missense	Exon 5 of 10	NP_001166206.1	Q96T49-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R16B	ENST00000299824.6	TSL:1 MANE Select	c.475G>A	p.Asp159Asn	missense	Exon 5 of 11	ENSP00000299824.1	Q96T49-1
	PPP1R16B	ENST00000969166.1		c.475G>A	p.Asp159Asn	missense	Exon 5 of 11	ENSP00000639225.1
	PPP1R16B	ENST00000969164.1		c.475G>A	p.Asp159Asn	missense	Exon 5 of 11	ENSP00000639223.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000159 AC: 23 AN: 1449686 Hom.: 0 Cov.: 30 AF XY: 0.0000180 AC XY: 13 AN XY: 720648

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32908

American (AMR) AF: 0.00 AC: 0 AN: 42888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25868

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38682

South Asian (SAS) AF: 0.00 AC: 0 AN: 83624

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000190 AC: 21 AN: 1106790

Other (OTH) AF: 0.00 AC: 0 AN: 59908

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000387232), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L
PhyloP100		8.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.36	N
REVEL	Benign	0.23
Sift	Benign	0.60	T
Sift4G	Benign	0.83	T
Polyphen		0.97	D
Vest4		0.76
MutPred		0.60		Loss of catalytic residue at D159 (P = 0.188)
MVP		0.70
MPC		2.4
ClinPred		0.77	D
GERP RS		5.0
Varity_R		0.15
gMVP		0.67
Mutation Taster		=52/48	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

dbSNP: rs866362326; hg19: chr20-37529231; COSMIC: COSV100239202; COSMIC: COSV100239202;