Genetic Variant RREB1:p.Lys29Lys (chr6-7181998-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_001003699.4(RREB1):c.87G>A(p.Lys29Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000662 in 1,613,814 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 5 hom. )

Consequence

RREB1
NM_001003699.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 2.09

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 6-7181998-G-A is Benign according to our data. Variant chr6-7181998-G-A is described in ClinVar as [Benign]. Clinvar id is 791535.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=2.09 with no splicing effect.

BS2

High AC in GnomAd4 at 410 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RREB1	NM_001003699.4 link	c.87G>A	p.Lys29Lys	synonymous_variant	Exon 4 of 13	ENST00000379938.7	NP_001003699.1	Q92766-2
RREB1	NM_001003698.4 link	c.87G>A	p.Lys29Lys	synonymous_variant	Exon 4 of 12		NP_001003698.1	Q92766-1A0A024QZU8
RREB1	NM_001168344.2 link	c.87G>A	p.Lys29Lys	synonymous_variant	Exon 4 of 12		NP_001161816.1	Q92766-1A0A024QZU8
RREB1	NM_001003700.2 link	c.87G>A	p.Lys29Lys	synonymous_variant	Exon 4 of 12		NP_001003700.1	Q92766-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RREB1	ENST00000379938.7 link	c.87G>A	p.Lys29Lys	synonymous_variant	Exon 4 of 13	1	NM_001003699.4	ENSP00000369270.2		Q92766-2

Frequencies

GnomAD3 genomes

AF:

0.00268

AC:

407

AN:

151826

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00923

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000983

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000804

AC:

202

AN:

251392

Hom.:

AF XY:

0.000662

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00947

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000451

AC:

659

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000433

AC XY:

315

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0106

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000149

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.00270

AC:

410

AN:

151944

Hom.:

Cov.:

AF XY:

0.00256

AC XY:

190

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00927

Gnomad4 AMR

AF:

0.000982

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.00123

Hom.:

Bravo

AF:

0.00308

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

RREB1-related disorder

Benign:1

Mar 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.7

DANN

Benign

0.77

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