12-15109322-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032918.3(RERG):c.388A>G(p.Thr130Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RERG NM_032918.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.20

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3370337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RERG	NM_032918.3	c.388A>G	p.Thr130Ala	missense_variant	5/5	ENST00000256953.6
RERG	NM_001190726.2	c.331A>G	p.Thr111Ala	missense_variant	4/4
RERG	XM_047429797.1	c.379A>G	p.Thr127Ala	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RERG	ENST00000256953.6	c.388A>G	p.Thr130Ala	missense_variant	5/5	1	NM_032918.3	P1
RERG	ENST00000538313.5	c.388A>G	p.Thr130Ala	missense_variant	4/4	1		P1
RERG	ENST00000536465.5	c.388A>G	p.Thr130Ala	missense_variant	5/5	3		P1
RERG	ENST00000546331.5	c.331A>G	p.Thr111Ala	missense_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251404 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.388A>G (p.T130A) alteration is located in exon 5 (coding exon 4) of the RERG gene. This alteration results from a A to G substitution at nucleotide position 388, causing the threonine (T) at amino acid position 130 to be replaced by an alanine (A). 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	0.070
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D;D;D;.
Eigen	Benign	-0.023
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.1	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N;N;N;D
REVEL	Benign	0.28
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.018	B;B;B;.
Vest4		0.46
MutPred		0.35		Loss of ubiquitination at K135 (P = 0.0618);Loss of ubiquitination at K135 (P = 0.0618);Loss of ubiquitination at K135 (P = 0.0618);.;
MVP		0.89
MPC		0.56
ClinPred		0.56	D
GERP RS		5.1
Varity_R		0.32
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs1192094527; hg19: chr12-15262256; COSMIC: COSV56999931; COSMIC: COSV56999931;