Genetic Variant NM_181333.4:c.321G>T (chr22-44726633-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_181333.4(PRR5):c.321G>T(p.Glu107Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

PRR5
NM_181333.4 missense, splice_region

Scores

Splicing: ADA: 0.0008915

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.03

Publications

1 publications found

Variant links:

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 links:

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-ARHGAP8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRR5	NM_181333.4	MANE Select	c.321G>T	p.Glu107Asp	missense splice_region	Exon 4 of 8	NP_851850.1	P85299-1
PRR5-ARHGAP8	NM_181334.6		c.321G>T	p.Glu107Asp	missense splice_region	Exon 4 of 15	NP_851851.3	B1AHC3
PRR5	NM_001198721.2		c.390G>T	p.Glu130Asp	missense splice_region	Exon 6 of 10	NP_001185650.1	P85299-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRR5	ENST00000336985.11	TSL:1 MANE Select	c.321G>T	p.Glu107Asp	missense splice_region	Exon 4 of 8	ENSP00000337464.6	P85299-1
PRR5-ARHGAP8	ENST00000352766.11	TSL:2	c.321G>T	p.Glu107Asp	missense splice_region	Exon 4 of 17	ENSP00000262731.11	B1AHC4
PRR5-ARHGAP8	ENST00000361473.9	TSL:5	c.321G>T	p.Glu107Asp	missense splice_region	Exon 4 of 15	ENSP00000354732.5	B1AHC3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-1.0

PhyloP100

3.0

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.7

REVEL

Benign

0.27

Sift

Benign

0.071

Sift4G

Benign

0.094

Polyphen

1.0

Vest4

0.71

MutPred

0.54

Loss of ubiquitination at K110 (P = 0.0896)

MVP

0.44

MPC

0.70

ClinPred

0.95

GERP RS

0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.086

gMVP

0.58

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00089

dbscSNV1_RF

Benign

0.15

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over