22-44702535-A-G

Variant names:

• chr22-44702535-A-G
• rs1486406837
• NM_181333.4:c.61A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181333.4(PRR5):​c.61A>G​(p.Arg21Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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: 0.0000015 (0 hom.)
• Consequence: PRR5 NM_181333.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16904369).

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.61A>G	p.Arg21Gly	missense	Exon 1 of 8	NP_851850.1	P85299-1
	PRR5-ARHGAP8	NM_181334.6		c.61A>G	p.Arg21Gly	missense	Exon 1 of 15	NP_851851.3	B1AHC3
	PRR5	NM_001198721.2		c.130A>G	p.Arg44Gly	missense	Exon 3 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.61A>G	p.Arg21Gly	missense	Exon 1 of 8	ENSP00000337464.6	P85299-1
	PRR5-ARHGAP8	ENST00000352766.11	TSL:2	c.61A>G	p.Arg21Gly	missense	Exon 1 of 17	ENSP00000262731.11	B1AHC4
	PRR5-ARHGAP8	ENST00000361473.9	TSL:5	c.61A>G	p.Arg21Gly	missense	Exon 1 of 15	ENSP00000354732.5	B1AHC3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000153 AC: 2 AN: 1309060 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 645574

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000763 AC: 2 AN: 26226

American (AMR) AF: 0.00 AC: 0 AN: 21988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22146

East Asian (EAS) AF: 0.00 AC: 0 AN: 28146

South Asian (SAS) AF: 0.00 AC: 0 AN: 69888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1036724

Other (OTH) AF: 0.00 AC: 0 AN: 53234

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151964 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74230

African (AFR) AF: 0.0000725 AC: 3 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.051
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.6
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.055
Sift	Benign	0.53	T
Sift4G	Benign	0.54	T
Polyphen		0.69	P
Vest4		0.18
MutPred		0.14		Gain of helix (P = 0.0199)
MVP		0.082
MPC		0.29
ClinPred		0.88	D
GERP RS		3.3
PromoterAI		-0.0016	Neutral
Varity_R		0.13
gMVP		0.25
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1486406837; hg19: chr22-45098415;