2-55573723-C-T

Position:

• chr2-55573723-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001122964.3(PPP4R3B):​c.1661G>A​(p.Cys554Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,390,354 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: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PPP4R3B NM_001122964.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

PPP4R3B (HGNC:29267): (protein phosphatase 4 regulatory subunit 3B) Predicted to act upstream of or within positive regulation of gluconeogenesis and protein dephosphorylation. Located in centrosome and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP4R3B	NM_001122964.3	c.1661G>A	p.Cys554Tyr	missense_variant	12/17	ENST00000616407.2	NP_001116436.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP4R3B	ENST00000616407.2	c.1661G>A	p.Cys554Tyr	missense_variant	12/17	1	NM_001122964.3	ENSP00000483228.1
PPP4R3B	ENST00000616288.4	c.1565G>A	p.Cys522Tyr	missense_variant	11/16	1		ENSP00000484116.1
PPP4R3B	ENST00000611717.4	c.1510+3592G>A		intron_variant		1		ENSP00000478677.1
PPP4R3B	ENST00000482826.1	n.-5G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1390354 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 685252

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: 9.29e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jul 15, 2021

The c.1661G>A (p.C554Y) alteration is located in exon 12 (coding exon 12) of the PPP4R3B gene. This alteration results from a G to A substitution at nucleotide position 1661, causing the cysteine (C) at amino acid position 554 to be replaced by a tyrosine (Y). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.7	.;M
PrimateAI	Pathogenic	0.92	D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.79		.;Gain of helix (P = 0.2059);
MVP		0.40
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.73
gMVP		0.74

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: rs1006605817; hg19: chr2-55800859;