chr22-44732356-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. Variant has been reported in ClinVar as Uncertain significance (★).

• 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181333.4. 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
	PRR5	NM_181333.4	MANE Select	c.520C>T	p.Pro174Ser	missense	Exon 6 of 8	NP_851850.1	P85299-1
	PRR5	NM_001198721.2		c.589C>T	p.Pro197Ser	missense	Exon 8 of 10	NP_001185650.1	P85299-5
	PRR5	NM_001017528.3		c.493C>T	p.Pro165Ser	missense	Exon 7 of 9	NP_001017528.1	P85299-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRR5	ENST00000336985.11	TSL:1 MANE Select	c.520C>T	p.Pro174Ser	missense	Exon 6 of 8	ENSP00000337464.6	P85299-1
	PRR5-ARHGAP8	ENST00000352766.11	TSL:2	c.520C>T	p.Pro174Ser	missense	Exon 6 of 17	ENSP00000262731.11	B1AHC4
	PRR5	ENST00000495017.5	TSL:1	n.1044C>T		non_coding_transcript_exon	Exon 2 of 4

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

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4918

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111610

Other (OTH) AF: 0.00 AC: 0 AN: 60234

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	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
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.9
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.46
Sift	Benign	0.18	T
Sift4G	Uncertain	0.041	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.54		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
Mutation Taster		=24/76	disease causing

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: rs1922174068; hg19: chr22-45128236;