PRR5 p.Phe123Leu

Variant names:

• chr22-44731776-C-A
• NM_181333.4:c.369C>A
• PRR5 p.Phe123Leu

Your query was ambiguous. Multiple possible variants found:

• chr22-44731776-C-A
• chr22-44731776-C-G
• chr22-44731774-T-C
• chr22-44731774-TTC-CTT
• chr22-44731774-TTC-CTA
• chr22-44731774-TTC-CTG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_181333.4(PRR5):​c.369C>A​(p.Phe123Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PRR5 NM_181333.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.02
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

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.369C>A	p.Phe123Leu	missense	Exon 5 of 8	NP_851850.1	P85299-1
	PRR5	NM_001198721.2		c.438C>A	p.Phe146Leu	missense	Exon 7 of 10	NP_001185650.1	P85299-5
	PRR5	NM_001017528.3		c.342C>A	p.Phe114Leu	missense	Exon 6 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.369C>A	p.Phe123Leu	missense	Exon 5 of 8	ENSP00000337464.6	P85299-1
	PRR5-ARHGAP8	ENST00000352766.11	TSL:2	c.369C>A	p.Phe123Leu	missense	Exon 5 of 17	ENSP00000262731.11	B1AHC4
	PRR5	ENST00000495017.5	TSL:1	n.893C>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.0
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.089	T
Varity_R		0.60
gMVP		0.75
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr22-45127656;