22-44732356-C-T

Variant names:

• chr22-44732356-C-T
• rs1922174068
• NM_181333.4:c.520C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_181333.4(PRR5):​c.520C>T​(p.Pro174Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,458,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PRR5 NM_181333.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.94

Genes affected

PRR5 (HGNC:31682): (proline rich 5) This gene encodes a protein with a proline-rich domain. This gene is located in a region of chromosome 22 reported to contain a tumor suppressor gene that may be involved in breast and colorectal tumorigenesis. The protein is a component of the mammalian target of rapamycin complex 2 (mTORC2), and it regulates platelet-derived growth factor (PDGF) receptor beta expression and PDGF signaling to Akt and S6K1. Alternative splicing and the use of alternative promoters results in transcripts encoding different isoforms. Read-through transcripts from this gene into the downstream Rho GTPase activating protein 8 (ARHGAP8) gene also exist, which led to the original description of PRR5 and ARHGAP8 being a single gene. [provided by RefSeq, Nov 2010]

PRR5-ARHGAP8 (HGNC:34512): (PRR5-ARHGAP8 readthrough) The PRR5-ARHGAP8 mRNA is an infrequent but naturally occurring read-through transcript of the neighboring proline rich 5, renal (PRR5) and Rho GTPase activating protein 8 (ARHGAP8) genes. The resulting fusion protein contains sequence identity with each individual gene product, and it includes domains characteristic of a RhoGAP protein. The significance of this read-through transcript and the function of its protein product have not yet been determined. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRR5	NM_181333.4	c.520C>T	p.Pro174Ser	missense_variant	Exon 6 of 8	ENST00000336985.11	NP_851850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRR5	ENST00000336985.11	c.520C>T	p.Pro174Ser	missense_variant	Exon 6 of 8	1	NM_181333.4	ENSP00000337464.6
PRR5-ARHGAP8	ENST00000352766.11	c.520C>T	p.Pro174Ser	missense_variant	Exon 6 of 17	2		ENSP00000262731.11

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458712 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725704

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.589C>T (p.P197S) alteration is located in exon 8 (coding exon 7) of the PRR5 gene. This alteration results from a C to T substitution at nucleotide position 589, causing the proline (P) at amino acid position 197 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	0.73
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	.;.;T;.;.;.;T;T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;.;.;D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.3	.;.;.;.;.;.;M;.;.
PROVEAN	Pathogenic	-5.9	.;.;D;.;D;D;D;D;D
REVEL	Uncertain	0.46
Sift	Benign	0.18	.;.;T;.;T;T;T;T;D
Sift4G	Uncertain	0.041	D;D;T;D;D;D;D;T;T
Polyphen		1.0, 1.0	.;.;.;.;.;.;D;.;D
Vest4		0.85
MutPred		0.54		.;.;.;.;.;.;Loss of catalytic residue at P174 (P = 0.0028);.;Loss of catalytic residue at P174 (P = 0.0028);
MVP		0.15
MPC		0.75
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.15
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs1922174068; hg19: chr22-45128236;