NM_174907.4:c.313T>A

Variant names:

• chr3-73059062-T-A
• NM_174907.4:c.313T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_174907.4(PPP4R2):​c.313T>A​(p.Cys105Ser) 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: 31)
• Consequence: PPP4R2 NM_174907.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.65
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP4R2	NM_174907.4	c.313T>A	p.Cys105Ser	missense_variant	Exon 4 of 9	ENST00000356692.10	NP_777567.1
PPP4R2	NM_001318026.2	c.199T>A	p.Cys67Ser	missense_variant	Exon 4 of 9		NP_001304955.1
PPP4R2	NM_001318025.2	c.142T>A	p.Cys48Ser	missense_variant	Exon 3 of 8		NP_001304954.1
PPP4R2	NM_001318027.2	c.-139T>A		5_prime_UTR_variant	Exon 3 of 8		NP_001304956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP4R2	ENST00000356692.10	c.313T>A	p.Cys105Ser	missense_variant	Exon 4 of 9	1	NM_174907.4	ENSP00000349124.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.313T>A (p.C105S) alteration is located in exon 4 (coding exon 4) of the PPP4R2 gene. This alteration results from a T to A substitution at nucleotide position 313, causing the cysteine (C) at amino acid position 105 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	0.95
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.069	D
MutationAssessor	Uncertain	2.6	M;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-8.2	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.010	D;D
Sift4G	Benign	0.18	T;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.92		Gain of disorder (P = 0.0198);Gain of disorder (P = 0.0198);
MVP		0.66
MPC		0.44
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.83
Mutation Taster		=62/38	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

hg19: chr3-73108213;