22-44679840-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001198721.2(PRR5):c.41C>T(p.Ser14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,598,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S14P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

PRR5
NM_001198721.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.516

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.024033576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons
PRR5	NM_001198721.2 linkuse as main transcript	c.41C>T	p.Ser14Leu	missense_variant	2/10
PRR5	NM_001017528.3 linkuse as main transcript	c.-11+11035C>T		intron_variant
PRR5	NM_001017529.3 linkuse as main transcript	c.-152+11035C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Appris	UniProt
PRR5	ENST00000403581.5 linkuse as main transcript	c.41C>T	p.Ser14Leu	missense_variant	2/10	2		P85299-5
PRR5	ENST00000006251.11 linkuse as main transcript	c.-11+2600C>T		intron_variant		2	A1	P85299-3
PRR5	ENST00000432186.5 linkuse as main transcript	c.-11+11035C>T		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000130

AC:

AN:

215296

Hom.:

AF XY:

0.000152

AC XY:

AN XY:

118526

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000284

Gnomad ASJ exome

AF:

0.000213

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000851

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000781

AC:

113

AN:

1446516

Hom.:

Cov.:

AF XY:

0.0000863

AC XY:

AN XY:

718194

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000281

Gnomad4 ASJ exome

AF:

0.0000774

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000275

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000498

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000110

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.000103

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

The c.41C>T (p.S14L) alteration is located in exon 2 (coding exon 1) of the PRR5 gene. This alteration results from a C to T substitution at nucleotide position 41, causing the serine (S) at amino acid position 14 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.68

Cadd

Benign

3.0

Dann

Benign

0.54

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.47

M_CAP

Benign

0.0015

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N

PROVEAN

Benign

-0.23

REVEL

Benign

0.039

Sift

Pathogenic

0.0

Vest4

0.14

MutPred

0.14

Loss of glycosylation at S14 (P = 0.0076);

MVP

0.043

MPC

0.16

ClinPred

0.081

GERP RS

-1.8

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over