3-73047262-C-T

Position:

• chr3-73047262-C-T

Variant summary

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

The NM_174907.4(PPP4R2):​c.193C>T​(p.Pro65Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: PPP4R2 NM_174907.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82

Genes affected

PPP4R2 (HGNC:18296): (protein phosphatase 4 regulatory subunit 2) The protein encoded by this gene is a regulatory subunit of the serine/threonine-protein phosphatase 4 complex. In addition to being required for efficient DNA double strand break repair, this complex plays a role in organization of microtubules at centrosomes and processing of spliceosomal snRNPs. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

PPP4R2 (HGNC:):

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, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP4R2	NM_174907.4	c.193C>T	p.Pro65Ser	missense_variant	3/9	ENST00000356692.10	NP_777567.1
PPP4R2	NM_001318026.2	c.79C>T	p.Pro27Ser	missense_variant	3/9		NP_001304955.1
PPP4R2	NM_001318025.2	c.117-11775C>T		intron_variant			NP_001304954.1
PPP4R2	NM_001318027.2	c.-164-11775C>T		intron_variant			NP_001304956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP4R2	ENST00000356692.10	c.193C>T	p.Pro65Ser	missense_variant	3/9	1	NM_174907.4	ENSP00000349124.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

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 03, 2022

The c.193C>T (p.P65S) alteration is located in exon 3 (coding exon 3) of the PPP4R2 gene. This alteration results from a C to T substitution at nucleotide position 193, causing the proline (P) at amino acid position 65 to be replaced by a serine (S). 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	0.97
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;T;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0050	D;D;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.66
MutPred		0.52		Loss of glycosylation at P70 (P = 0.0137);Loss of glycosylation at P70 (P = 0.0137);.;
MVP		0.40
MPC		0.14
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.64
gMVP		0.46

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: rs1188310548; hg19: chr3-73096413;