22-44726633-G-T

Position:

• chr22-44726633-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRR5	NM_181333.4	c.321G>T	p.Glu107Asp	missense_variant, splice_region_variant	4/8	ENST00000336985.11
PRR5-ARHGAP8	NM_181334.6	c.321G>T	p.Glu107Asp	missense_variant, splice_region_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRR5	ENST00000336985.11	c.321G>T	p.Glu107Asp	missense_variant, splice_region_variant	4/8	1	NM_181333.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Dec 06, 2021

The c.390G>T (p.E130D) alteration is located in exon 6 (coding exon 5) of the PRR5 gene. This alteration results from a G to T substitution at nucleotide position 390, causing the glutamic acid (E) at amino acid position 130 to be replaced by an aspartic acid (D). 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	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D;.;.;D;D;T;D;T;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;D;D;D;D;N;N
PrimateAI	Pathogenic	0.83	D
Sift4G	Benign	0.094	T;D;T;D;T;T;T;T;T;D;T
Polyphen		1.0, 1.0, 0.99	.;.;.;.;.;.;D;.;.;D;D
Vest4		0.71
MutPred		0.54		.;.;.;.;.;.;Loss of ubiquitination at K110 (P = 0.0896);Loss of ubiquitination at K110 (P = 0.0896);.;Loss of ubiquitination at K110 (P = 0.0896);Loss of ubiquitination at K110 (P = 0.0896);
MVP		0.44
MPC		0.70
ClinPred		0.95	D
GERP RS		0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.086
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs28450358; hg19: chr22-45122513;