22-44736951-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_181333.4(PRR5):c.871G>A(p.Glu291Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00539 in 1,605,058 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0058 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (42 hom.)
• Consequence: PRR5 NM_181333.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.25

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:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050508976).
• BP6: Variant 22-44736951-G-A is Benign according to our data. Variant chr22-44736951-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2653275.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRR5	NM_181333.4	c.871G>A	p.Glu291Lys	missense_variant	8/8	ENST00000336985.11
PRR5-ARHGAP8	NM_181334.6	c.322+10317G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRR5	ENST00000336985.11	c.871G>A	p.Glu291Lys	missense_variant	8/8	1	NM_181333.4	P4

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 885 AN: 152202 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0349

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00585

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00625 AC: 1472 AN: 235456 Hom.: 15 AF XY: 0.00648 AC XY: 841 AN XY: 129704

Gnomad AFR exome AF: 0.000823

Gnomad AMR exome AF: 0.00155

Gnomad ASJ exome AF: 0.00380

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000824

Gnomad FIN exome AF: 0.0316

Gnomad NFE exome AF: 0.00707

Gnomad OTH exome AF: 0.00648

GnomAD4 exome AF: 0.00534 AC: 7760 AN: 1452738 Hom.: 42 Cov.: 32 AF XY: 0.00533 AC XY: 3847 AN XY: 722276

Gnomad4 AFR exome AF: 0.000659

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.00368

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000755

Gnomad4 FIN exome AF: 0.0278

Gnomad4 NFE exome AF: 0.00529

Gnomad4 OTH exome AF: 0.00445

GnomAD4 genome AF: 0.00580 AC: 884 AN: 152320 Hom.: 12 Cov.: 33 AF XY: 0.00701 AC XY: 522 AN XY: 74486

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0349

Gnomad4 NFE AF: 0.00585

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00525 Hom.: 1

Bravo AF: 0.00355

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00184 AC: 8

ESP6500EA AF: 0.00656 AC: 56

ExAC AF: 0.00643 AC: 773

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

PRR5: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;.;.;D;D
MetaRNN	Benign	0.0051	T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D
Vest4		0.41
MVP		0.21
MPC		0.32
ClinPred		0.024	T
GERP RS		5.0
Varity_R		0.20
gMVP		0.65

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: rs56299305; hg19: chr22-45132831;