22-44732338-C-T

Position:

• chr22-44732338-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_181333.4(PRR5):​c.502C>T​(p.Arg168Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00185 in 1,612,062 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: PRR5 NM_181333.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.29

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]

PRR5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033712894).
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRR5	NM_181333.4	c.502C>T	p.Arg168Trp	missense_variant	6/8	ENST00000336985.11	NP_851850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRR5	ENST00000336985.11	c.502C>T	p.Arg168Trp	missense_variant	6/8	1	NM_181333.4	ENSP00000337464.6
PRR5-ARHGAP8	ENST00000352766.11	c.502C>T	p.Arg168Trp	missense_variant	6/17	2		ENSP00000262731.11

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152222 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00108 AC: 270 AN: 249410 Hom.: 1 AF XY: 0.00103 AC XY: 139 AN XY: 135420

Gnomad AFR exome AF: 0.000498

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00229

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00112

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.00192 AC: 2809 AN: 1459722 Hom.: 6 Cov.: 31 AF XY: 0.00186 AC XY: 1353 AN XY: 726234

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00118

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000765

Gnomad4 NFE exome AF: 0.00237

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152340 Hom.: 0 Cov.: 34 AF XY: 0.00107 AC XY: 80 AN XY: 74482

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00157 Hom.: 0

Bravo AF: 0.000986

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000981 AC: 119

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00184

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2024

The c.571C>T (p.R191W) 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 571, causing the arginine (R) at amino acid position 191 to be replaced by a tryptophan (W). 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	Uncertain	0.35
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	.;.;T;.;.;.;T;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Benign	0.67	D
LIST_S2	Pathogenic	0.97	D;D;D;.;.;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.034	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.4	.;.;.;.;.;.;M;.;.
PROVEAN	Uncertain	-3.4	.;.;D;.;D;D;D;D;D
REVEL	Uncertain	0.57
Sift	Benign	0.071	.;.;T;.;D;D;D;T;D
Sift4G	Benign	0.12	T;D;T;D;T;T;T;T;D
Polyphen		1.0	.;.;.;.;.;.;D;.;D
Vest4		0.76
MVP		0.52
MPC		0.76
ClinPred		0.068	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.12
gMVP		0.62

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: rs150104103; hg19: chr22-45128218;