Genetic Variant NM_032918.3:c.166A>G (chr12-15111370-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032918.3(RERG):c.166A>G(p.Met56Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M56L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

RERG
NM_032918.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.09

Variant links:

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]

RERG links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
RERG	NM_032918.3 link	c.166A>G	p.Met56Val	missense_variant	Exon 4 of 5	ENST00000256953.6	NP_116307.1	Q96A58-1A0A024RAT4
RERG	NM_001190726.2 link	c.109A>G	p.Met37Val	missense_variant	Exon 3 of 4		NP_001177655.1	Q96A58-2
RERG	XM_047429797.1 link	c.157A>G	p.Met53Val	missense_variant	Exon 4 of 5		XP_047285753.1
RERG	XM_047429798.1 link	c.330A>G	p.Pro110Pro	synonymous_variant	Exon 5 of 6		XP_047285754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RERG	ENST00000256953.6 link	c.166A>G	p.Met56Val	missense_variant	Exon 4 of 5	1	NM_032918.3	ENSP00000256953.2		Q96A58-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461082

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726892

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.166A>G (p.M56V) alteration is located in exon 4 (coding exon 3) of the RERG gene. This alteration results from a A to G substitution at nucleotide position 166, causing the methionine (M) at amino acid position 56 to be replaced by a valine (V). 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

Benign

0.19

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

T;T;T;.;.;.

Eigen

Benign

-0.15

Eigen_PC

Benign

0.087

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

.;.;D;D;D;D

M_CAP

Benign

0.058

MetaRNN

Uncertain

0.61

D;D;D;D;D;D

MetaSVM

Benign

-0.84

MutationAssessor

Benign

-0.29

N;N;N;.;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.8

N;N;N;N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.032

D;D;D;D;D;T

Sift4G

Benign

0.094

T;T;T;T;.;T

Polyphen

0.024

B;B;B;.;.;.

Vest4

0.63

MutPred

0.61

Loss of phosphorylation at T61 (P = 0.0974);Loss of phosphorylation at T61 (P = 0.0974);Loss of phosphorylation at T61 (P = 0.0974);.;.;Loss of phosphorylation at T61 (P = 0.0974);

MVP

0.81

MPC

0.38

ClinPred

0.93

GERP RS

4.1

Varity_R

0.55

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over