12-15109415-T-C

Variant names:

• chr12-15109415-T-C
• rs780125717
• NM_032918.3:c.295A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032918.3(RERG):​c.295A>G​(p.Lys99Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,864 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K99Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RERG NM_032918.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.08
• Publications: 0 publications found

Genes affected

RERG (HGNC:15980): (RAS like estrogen regulated growth inhibitor) RERG, a member of the RAS superfamily of GTPases, inhibits cell proliferation and tumor formation (Finlin et al., 2001 [PubMed 11533059]).[supplied by OMIM, Mar 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032918.3. 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
	RERG	NM_032918.3	MANE Select	c.295A>G	p.Lys99Glu	missense	Exon 5 of 5	NP_116307.1	Q96A58-1
	RERG	NM_001190726.2		c.238A>G	p.Lys80Glu	missense	Exon 4 of 4	NP_001177655.1	Q96A58-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RERG	ENST00000256953.6	TSL:1 MANE Select	c.295A>G	p.Lys99Glu	missense	Exon 5 of 5	ENSP00000256953.2	Q96A58-1
	RERG	ENST00000538313.5	TSL:1	c.295A>G	p.Lys99Glu	missense	Exon 4 of 4	ENSP00000441505.1	Q96A58-1
	RERG	ENST00000536465.5	TSL:3	c.295A>G	p.Lys99Glu	missense	Exon 5 of 5	ENSP00000438280.1	Q96A58-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727238

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.51
Sift	Benign	0.11	T
Sift4G	Benign	0.21	T
Polyphen		0.37	B
Vest4		0.44
MutPred		0.52		Loss of ubiquitination at K99 (P = 0.0148)
MVP		0.92
MPC		1.2
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.85
gMVP		0.54
Mutation Taster		=67/33	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: rs780125717; hg19: chr12-15262349;