chr20-38900588-G-A

Position:

• chr20-38900588-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

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. 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

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP1R16B	NM_015568.4	c.475G>A	p.Asp159Asn	missense_variant	5/11	ENST00000299824.6	NP_056383.1
PPP1R16B	NM_001172735.3	c.475G>A	p.Asp159Asn	missense_variant	5/10		NP_001166206.1
PPP1R16B	XM_011528768.4	c.487G>A	p.Asp163Asn	missense_variant	4/10		XP_011527070.1
PPP1R16B	XM_047440086.1	c.-26-2080G>A		intron_variant			XP_047296042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1R16B	ENST00000299824.6	c.475G>A	p.Asp159Asn	missense_variant	5/11	1	NM_015568.4	ENSP00000299824	P1
PPP1R16B	ENST00000373331.2	c.475G>A	p.Asp159Asn	missense_variant	5/10	5		ENSP00000362428

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000190

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2022

The c.475G>A (p.D159N) alteration is located in exon 5 (coding exon 4) of the PPP1R16B gene. This alteration results from a G to A substitution at nucleotide position 475, causing the aspartic acid (D) at amino acid position 159 to be replaced by an asparagine (N). 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	0.15
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;D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.36	N;N
REVEL	Benign	0.23
Sift	Benign	0.60	T;T
Sift4G	Benign	0.83	T;T
Polyphen		0.97	D;.
Vest4		0.76
MutPred		0.60		Loss of catalytic residue at D159 (P = 0.188);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

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