22-44734493-A-G

Position:

• chr22-44734493-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181333.4(PRR5):​c.556-534A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 152,700 control chromosomes in the GnomAD database, including 25,404 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 0.54 (25273 hom., cov: 33)
  • Exomes 𝑓: 0.66 (131 hom.)
• Consequence: PRR5 NM_181333.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.188

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRR5	NM_181333.4	c.556-534A>G		intron_variant		ENST00000336985.11	NP_851850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRR5	ENST00000336985.11	c.556-534A>G		intron_variant		1	NM_181333.4	ENSP00000337464.6
PRR5-ARHGAP8	ENST00000352766.11	c.556-534A>G		intron_variant		2		ENSP00000262731.11

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81807 AN: 152002 Hom.: 25257 Cov.: 33

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.691

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.724

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.699

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.592

GnomAD4 exome AF: 0.659 AC: 382 AN: 580 Hom.: 131 Cov.: 0 AF XY: 0.621 AC XY: 169 AN XY: 272

Gnomad4 AFR exome AF: 0.375

Gnomad4 AMR exome AF: 0.597

Gnomad4 ASJ exome AF: 0.750

Gnomad4 EAS exome AF: 0.200

Gnomad4 SAS exome AF: 0.357

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.697

Gnomad4 OTH exome AF: 0.700

GnomAD4 genome AF: 0.538 AC: 81845 AN: 152120 Hom.: 25273 Cov.: 33 AF XY: 0.541 AC XY: 40206 AN XY: 74356

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.608

Gnomad4 ASJ AF: 0.724

Gnomad4 EAS AF: 0.291

Gnomad4 SAS AF: 0.627

Gnomad4 FIN AF: 0.699

Gnomad4 NFE AF: 0.685

Gnomad4 OTH AF: 0.595

Alfa AF: 0.533 Hom.: 2873

Bravo AF: 0.516

Asia WGS AF: 0.453 AC: 1576 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.44

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: rs132404; hg19: chr22-45130373;