NM_181333.4:c.166C>A

Variant names:

• chr22-44714622-C-A
• rs587777903
• NM_181333.4:c.166C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181333.4(PRR5):​c.166C>A​(p.Arg56Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRR5 NM_181333.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.58
• Publications: 0 publications found

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: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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26706517).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRR5	NM_181333.4	MANE Select	c.166C>A	p.Arg56Ser	missense	Exon 2 of 8	NP_851850.1	P85299-1
	PRR5-ARHGAP8	NM_181334.6		c.166C>A	p.Arg56Ser	missense	Exon 2 of 15	NP_851851.3	B1AHC3
	PRR5	NM_001198721.2		c.235C>A	p.Arg79Ser	missense	Exon 4 of 10	NP_001185650.1	P85299-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRR5	ENST00000336985.11	TSL:1 MANE Select	c.166C>A	p.Arg56Ser	missense	Exon 2 of 8	ENSP00000337464.6	P85299-1
	PRR5-ARHGAP8	ENST00000352766.11	TSL:2	c.166C>A	p.Arg56Ser	missense	Exon 2 of 17	ENSP00000262731.11	B1AHC4
	PRR5-ARHGAP8	ENST00000361473.9	TSL:5	c.166C>A	p.Arg56Ser	missense	Exon 2 of 15	ENSP00000354732.5	B1AHC3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461370 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726986

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T
Eigen	Benign	0.077
Eigen_PC	Benign	0.086
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.25
Sift	Benign	0.17	T
Sift4G	Benign	0.14	T
Polyphen		0.91	P
Vest4		0.71
MutPred		0.58		Loss of methylation at K57 (P = 0.052)
MVP		0.10
MPC		0.76
ClinPred		0.86	D
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.34
Mutation Taster		=60/40	polymorphism

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

Other links and lift over

dbSNP: rs587777903; hg19: chr22-45110502;