NM_005040.4:c.717G>T

Variant names:

• chr11-82849948-C-A
• rs377663573
• NM_005040.4:c.717G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005040.4(PRCP):​c.717G>T​(p.Arg239Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000196 in 1,528,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: PRCP NM_005040.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.86
• Publications: 1 publications found

Genes affected

PRCP (HGNC:9344): (prolylcarboxypeptidase) This gene encodes a member of the peptidase S28 family of serine exopeptidases. The encoded preproprotein is proteolytically processed to generate the mature lysosomal prolylcarboxypeptidase. This enzyme cleaves C-terminal amino acids linked to proline in peptides such as angiotension II, III and des-Arg9-bradykinin. The cleavage occurs at acidic pH, but the enzyme activity is retained with some substrates at neutral pH. This enzyme has been shown to be an activator of the cell matrix-associated prekallikrein. The importance of angiotension II, one of the substrates of this enzyme, in regulating blood pressure and electrolyte balance suggests that this gene may be related to essential hypertension. A pseudogene of this gene has been identified on chromosome 2. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1794971).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005040.4. 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
	PRCP	NM_005040.4	MANE Select	c.717G>T	p.Arg239Ser	missense	Exon 5 of 9	NP_005031.1	P42785-1
	PRCP	NM_199418.4		c.780G>T	p.Arg260Ser	missense	Exon 6 of 10	NP_955450.2	P42785-2
	PRCP	NM_001319214.2		c.402G>T	p.Arg134Ser	missense	Exon 4 of 8	NP_001306143.1	B7Z7Q6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRCP	ENST00000313010.8	TSL:1 MANE Select	c.717G>T	p.Arg239Ser	missense	Exon 5 of 9	ENSP00000317362.3	P42785-1
	PRCP	ENST00000393399.6	TSL:2	c.780G>T	p.Arg260Ser	missense	Exon 6 of 10	ENSP00000377055.2	P42785-2
	PRCP	ENST00000949391.1		c.717G>T	p.Arg239Ser	missense	Exon 5 of 9	ENSP00000619450.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1376056 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 683564

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000338 AC: 1 AN: 29556

American (AMR) AF: 0.00 AC: 0 AN: 34328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23964

East Asian (EAS) AF: 0.00 AC: 0 AN: 34878

South Asian (SAS) AF: 0.00 AC: 0 AN: 72272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5470

European-Non Finnish (NFE) AF: 9.36e-7 AC: 1 AN: 1068492

Other (OTH) AF: 0.00 AC: 0 AN: 56148

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74292

African (AFR) AF: 0.0000242 AC: 1 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2090

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	Benign	0.16
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	5.0
DANN	Benign	0.93
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.9
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.40
Sift	Benign	0.34	T
Sift4G	Benign	0.34	T
Polyphen		0.039	B
Vest4		0.34
MutPred		0.47		Gain of disorder (P = 0.0418)
MVP		0.89
MPC		0.031
ClinPred		0.11	T
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.66
Mutation Taster		=77/23	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

dbSNP: rs377663573; hg19: chr11-82560990;