22-44702535-A-T

Variant names:

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

Variant summary

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

The NM_181333.4(PRR5):​c.61A>T​(p.Arg21*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000764 in 1,309,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: PRR5 NM_181333.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

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

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>T	p.Arg21*	stop_gained	Exon 1 of 8	NP_851850.1	P85299-1
	PRR5-ARHGAP8	NM_181334.6		c.61A>T	p.Arg21*	stop_gained	Exon 1 of 15	NP_851851.3	B1AHC3
	PRR5	NM_001198721.2		c.130A>T	p.Arg44*	stop_gained	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>T	p.Arg21*	stop_gained	Exon 1 of 8	ENSP00000337464.6	P85299-1
	PRR5-ARHGAP8	ENST00000352766.11	TSL:2	c.61A>T	p.Arg21*	stop_gained	Exon 1 of 17	ENSP00000262731.11	B1AHC4
	PRR5-ARHGAP8	ENST00000361473.9	TSL:5	c.61A>T	p.Arg21*	stop_gained	Exon 1 of 15	ENSP00000354732.5	B1AHC3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.64e-7 AC: 1 AN: 1309060 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 645574

African (AFR) AF: 0.00 AC: 0 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: 9.65e-7 AC: 1 AN: 1036724

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.80	D
PhyloP100		2.6
Vest4		0.19
GERP RS		3.3
PromoterAI		-0.039	Neutral
Mutation Taster		=10/190	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;