22-44732312-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181333.4(PRR5):c.476G>A(p.Ser159Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 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. S159G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PRR5 NM_181333.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.29

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2503368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRR5	NM_181333.4	c.476G>A	p.Ser159Asn	missense_variant	6/8	ENST00000336985.11
PRR5-ARHGAP8	NM_181334.6	c.322+5678G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRR5	ENST00000336985.11	c.476G>A	p.Ser159Asn	missense_variant	6/8	1	NM_181333.4	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.545G>A (p.S182N) alteration is located in exon 8 (coding exon 7) of the PRR5 gene. This alteration results from a G to A substitution at nucleotide position 545, causing the serine (S) at amino acid position 182 to be replaced by an asparagine (N). 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	0.16
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	20
Dann	Benign	0.91
Eigen	Benign	0.024
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.86	D;D;T;.;.;D;D;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N;D;D;D;D;D;N
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.11	.;.;.;.;.;.;B;.;.;B
Vest4		0.18
MutPred		0.59		.;.;.;.;.;.;Loss of sheet (P = 0.0126);.;.;Loss of sheet (P = 0.0126);
MVP		0.068
MPC		0.18
ClinPred		0.31	T
GERP RS		3.6
Varity_R		0.036
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-45128192;