20-38918572-A-G

Variant names:

• chr20-38918572-A-G
• NM_015568.4:c.1610A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015568.4(PPP1R16B):​c.1610A>G​(p.Tyr537Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,393,546 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PPP1R16B NM_015568.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R16B	NM_015568.4	c.1610A>G	p.Tyr537Cys	missense_variant	Exon 11 of 11	ENST00000299824.6	NP_056383.1
PPP1R16B	NM_001172735.3	c.1484A>G	p.Tyr495Cys	missense_variant	Exon 10 of 10		NP_001166206.1
PPP1R16B	XM_011528768.4	c.1622A>G	p.Tyr541Cys	missense_variant	Exon 10 of 10		XP_011527070.1
PPP1R16B	XM_047440086.1	c.1013A>G	p.Tyr338Cys	missense_variant	Exon 7 of 7		XP_047296042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R16B	ENST00000299824.6	c.1610A>G	p.Tyr537Cys	missense_variant	Exon 11 of 11	1	NM_015568.4	ENSP00000299824.1
PPP1R16B	ENST00000373331.2	c.1484A>G	p.Tyr495Cys	missense_variant	Exon 10 of 10	5		ENSP00000362428.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1393546 Hom.: 0 Cov.: 31 AF XY: 0.00000292 AC XY: 2 AN XY: 685396

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: 0.00

Gnomad4 OTH exome AF: 0.0000349

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1610A>G (p.Y537C) alteration is located in exon 11 (coding exon 10) of the PPP1R16B gene. This alteration results from a A to G substitution at nucleotide position 1610, causing the tyrosine (Y) at amino acid position 537 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0070	D;T
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.76
MutPred		0.36		Loss of phosphorylation at Y537 (P = 0.0282);.;
MVP		0.73
MPC		1.5
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.29
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-37547215; COSMIC: COSV100240344;