chr18-9553343-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042388.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP4R1	NM_001042388.3	MANE Select	c.2270G>A	p.Arg757Gln	missense	Exon 16 of 20	NP_001035847.1	Q8TF05-1
	PPP4R1	NM_005134.4		c.2219G>A	p.Arg740Gln	missense	Exon 16 of 20	NP_005125.1	Q8TF05-2
	PPP4R1	NM_001382562.1		c.2003G>A	p.Arg668Gln	missense	Exon 15 of 19	NP_001369491.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP4R1	ENST00000400556.8	TSL:1 MANE Select	c.2270G>A	p.Arg757Gln	missense	Exon 16 of 20	ENSP00000383402.3	Q8TF05-1
	PPP4R1	ENST00000400555.7	TSL:1	c.2219G>A	p.Arg740Gln	missense	Exon 16 of 20	ENSP00000383401.3	Q8TF05-2
	PPP4R1	ENST00000886291.1		c.2270G>A	p.Arg757Gln	missense	Exon 16 of 20	ENSP00000556350.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 248742 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 33064

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 85896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000100 AC: 11 AN: 1096526

Other (OTH) AF: 0.00 AC: 0 AN: 59846

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	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
Mutation Taster		=37/63	disease causing

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

Other links and lift over

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