18-9553343-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_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

Scores

8
8
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.09
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
PPP4R1NM_001042388.3 linkc.2270G>A p.Arg757Gln missense_variant Exon 16 of 20 ENST00000400556.8 NP_001035847.1 Q8TF05-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PPP4R1ENST00000400556.8 linkc.2270G>A p.Arg757Gln missense_variant Exon 16 of 20 1 NM_001042388.3 ENSP00000383402.3 Q8TF05-1

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
show subpopulations
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
LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1389034923; hg19: chr18-9553341; COSMIC: COSV53284075; COSMIC: COSV53284075; API