18-9553343-C-T

Variant names:

• chr18-9553343-C-T
• rs1389034923
• NM_001042388.3:c.2270G>A

Variant summary

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

The NM_001042388.3(PPP4R1):​c.2270G>A​(p.Arg757Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000762 in 1,444,224 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: 0.0000076 (0 hom.)
• Consequence: PPP4R1 NM_001042388.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.09

Genes affected

PPP4R1 (HGNC:9320): (protein phosphatase 4 regulatory subunit 1) This gene encodes one of several alternate regulatory subunits of serine/threonine protein phosphatase 4 (PP4). The protein features multiple HEAT repeats. This protein forms a complex with PP4RC. This complex may have a distinct role from other PP4 complexes, including regulation of HDAC3 (Zhang et al., PMID: 15805470). There is also a transcribed pseudogene on chromosome 20. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

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, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP4R1	NM_001042388.3	c.2270G>A	p.Arg757Gln	missense_variant	Exon 16 of 20	ENST00000400556.8	NP_001035847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP4R1	ENST00000400556.8	c.2270G>A	p.Arg757Gln	missense_variant	Exon 16 of 20	1	NM_001042388.3	ENSP00000383402.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000762 AC: 11 AN: 1444224 Hom.: 0 Cov.: 30 AF XY: 0.00000695 AC XY: 5 AN XY: 719574

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: 0.0000100

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2270G>A (p.R757Q) alteration is located in exon 16 (coding exon 16) of the PPP4R1 gene. This alteration results from a G to A substitution at nucleotide position 2270, causing the arginine (R) at amino acid position 757 to be replaced by a glutamine (Q). 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	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.74		Loss of loop (P = 0.0203);.;
MVP		0.55
MPC		1.9
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.79
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1389034923; hg19: chr18-9553341; COSMIC: COSV53284075; COSMIC: COSV53284075;