Genetic Variant PRR5L:p.Ala259Val (chr11-36462405-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_001160167.2(PRR5L):c.776C>T(p.Ala259Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000485 in 1,568,310 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 1 hom. )

Consequence

PRR5L
NM_001160167.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.457

Variant links:

Genes affected

PRR5L (HGNC:25878): (proline rich 5 like) Enables ubiquitin protein ligase binding activity. Involved in several processes, including TORC2 signaling; positive regulation of mRNA catabolic process; and regulation of fibroblast migration. Part of TORC2 complex. [provided by Alliance of Genome Resources, Apr 2022]

PRR5L links:

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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=0.023208678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRR5L	NM_001160167.2 link	c.776C>T	p.Ala259Val	missense_variant	Exon 9 of 9	ENST00000530639.6	NP_001153639.1	Q6MZQ0-1B3KNU3
PRR5L	NM_024841.5 link	c.776C>T	p.Ala259Val	missense_variant	Exon 10 of 10		NP_079117.3	Q6MZQ0-1
PRR5L	NM_001160168.2 link	c.392C>T	p.Ala131Val	missense_variant	Exon 6 of 6		NP_001153640.1	Q6MZQ0-3
PRR5L	NM_001160169.1 link	c.*31C>T		3_prime_UTR_variant	Exon 7 of 7		NP_001153641.1	Q6MZQ0-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRR5L	ENST00000530639.6 link	c.776C>T	p.Ala259Val	missense_variant	Exon 9 of 9	2	NM_001160167.2	ENSP00000435050.1		Q6MZQ0-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000786

AC:

AN:

216156

Hom.:

AF XY:

0.0000954

AC XY:

AN XY:

115316

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000472

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000514

Gnomad OTH exome

AF:

0.000191

GnomAD4 exome

AF:

0.0000516

AC:

AN:

1415994

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

698560

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000506

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000221

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000907

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.776C>T (p.A259V) alteration is located in exon 9 (coding exon 8) of the PRR5L gene. This alteration results from a C to T substitution at nucleotide position 776, causing the alanine (A) at amino acid position 259 to be replaced by a valine (V). 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

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.0010

T;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.49

.;T

M_CAP

Benign

0.0059

MetaRNN

Benign

0.023

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.060

N;N

REVEL

Benign

0.070

Sift

Benign

0.37

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.013

B;B

Vest4

0.051

MutPred

0.32

Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);

MVP

0.20

MPC

0.27

ClinPred

0.034

GERP RS

4.3

Varity_R

0.066

gMVP

0.22

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