Variant 6-7189208-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001003699.4(RREB1):c.311A>G(p.Lys104Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,196 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: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

RREB1
NM_001003699.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.62

Variant links:

Genes affected

RREB1 (HGNC:10449): (ras responsive element binding protein 1) The protein encoded by this gene is a zinc finger transcription factor that binds to RAS-responsive elements (RREs) of gene promoters. It has been shown that the calcitonin gene promoter contains an RRE and that the encoded protein binds there and increases expression of calcitonin, which may be involved in Ras/Raf-mediated cell differentiation. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

RREB1 links:

RREB1 (HGNC:):

RREB1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RREB1	NM_001003699.4 linkuse as main transcript	c.311A>G	p.Lys104Arg	missense_variant	6/13	ENST00000379938.7	NP_001003699.1	Q92766-2
RREB1	NM_001003698.4 linkuse as main transcript	c.311A>G	p.Lys104Arg	missense_variant	6/12		NP_001003698.1	Q92766-1A0A024QZU8
RREB1	NM_001168344.2 linkuse as main transcript	c.311A>G	p.Lys104Arg	missense_variant	6/12		NP_001161816.1	Q92766-1A0A024QZU8
RREB1	NM_001003700.2 linkuse as main transcript	c.311A>G	p.Lys104Arg	missense_variant	6/12		NP_001003700.1	Q92766-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RREB1	ENST00000379938.7 linkuse as main transcript	c.311A>G	p.Lys104Arg	missense_variant	6/13	1	NM_001003699.4	ENSP00000369270.2		Q92766-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2024

The c.311A>G (p.K104R) alteration is located in exon 6 (coding exon 3) of the RREB1 gene. This alteration results from a A to G substitution at nucleotide position 311, causing the lysine (K) at amino acid position 104 to be replaced by an arginine (R). 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

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

T;T;.;.;.;T;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;D;D;D;D;D;D

M_CAP

Benign

0.040

MetaRNN

Pathogenic

0.76

D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.2

M;.;M;.;M;M;.

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.7

D;D;D;D;D;D;D

REVEL

Benign

0.27

Sift

Pathogenic

0.0

D;T;D;T;T;D;D

Sift4G

Uncertain

0.028

D;D;D;T;D;D;T

Polyphen

0.98

D;.;D;.;D;D;.

Vest4

0.65

MutPred

0.60

Loss of ubiquitination at K104 (P = 0.0098);Loss of ubiquitination at K104 (P = 0.0098);Loss of ubiquitination at K104 (P = 0.0098);Loss of ubiquitination at K104 (P = 0.0098);Loss of ubiquitination at K104 (P = 0.0098);Loss of ubiquitination at K104 (P = 0.0098);Loss of ubiquitination at K104 (P = 0.0098);

MVP

0.79

MPC

1.3

ClinPred

0.99

GERP RS

5.7

Varity_R

0.65

gMVP

0.54

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

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