6-7189165-A-G

Position:

chr6-7189165-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000379938.7(RREB1):c.268A>G(p.Thr90Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,612,772 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0080 ( 13 hom., cov: 32)

Exomes 𝑓: 0.00089 ( 12 hom. )

Consequence

RREB1
ENST00000379938.7 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 2.88

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0076525807).

BP6

Variant 6-7189165-A-G is Benign according to our data. Variant chr6-7189165-A-G is described in ClinVar as [Benign]. Clinvar id is 768060.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-7189165-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00802 (1222/152296) while in subpopulation AFR AF= 0.0281 (1168/41552). AF 95% confidence interval is 0.0268. There are 13 homozygotes in gnomad4. There are 572 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1222 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RREB1	NM_001003699.4 linkuse as main transcript	c.268A>G	p.Thr90Ala	missense_variant	6/13	ENST00000379938.7	NP_001003699.1
RREB1	NM_001003698.4 linkuse as main transcript	c.268A>G	p.Thr90Ala	missense_variant	6/12		NP_001003698.1
RREB1	NM_001168344.2 linkuse as main transcript	c.268A>G	p.Thr90Ala	missense_variant	6/12		NP_001161816.1
RREB1	NM_001003700.2 linkuse as main transcript	c.268A>G	p.Thr90Ala	missense_variant	6/12		NP_001003700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RREB1	ENST00000379938.7 linkuse as main transcript	c.268A>G	p.Thr90Ala	missense_variant	6/13	1	NM_001003699.4	ENSP00000369270	P1	Q92766-2

Frequencies

GnomAD3 genomes

AF:

0.00802

AC:

1220

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0282

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00227

AC:

566

AN:

249310

Hom.:

AF XY:

0.00159

AC XY:

214

AN XY:

134802

show subpopulations

Gnomad AFR exome

AF:

0.0291

Gnomad AMR exome

AF:

0.00206

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:

0.000159

Gnomad OTH exome

AF:

0.000821

GnomAD4 exome

AF:

0.000889

AC:

1299

AN:

1460476

Hom.:

Cov.:

AF XY:

0.000780

AC XY:

567

AN XY:

726542

show subpopulations

Gnomad4 AFR exome

AF:

0.0289

Gnomad4 AMR exome

AF:

0.00237

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000382

Gnomad4 NFE exome

AF:

0.0000818

Gnomad4 OTH exome

AF:

0.00202

GnomAD4 genome

AF:

0.00802

AC:

1222

AN:

152296

Hom.:

Cov.:

AF XY:

0.00768

AC XY:

572

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0281

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00117

Hom.:

Bravo

AF:

0.00911

ESP6500AA

AF:

0.0281

AC:

124

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00273

AC:

331

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

RREB1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.036

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

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.78

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

MetaRNN

Benign

0.0077

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.93

L;.;L;.;L;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.8

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

REVEL

Benign

0.10

Sift

Benign

0.062

T;T;T;T;T;T;T

Sift4G

Pathogenic

0.0

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

Polyphen

0.99

D;.;P;.;D;D;.

Vest4

0.22

MVP

0.44

MPC

0.72

ClinPred

0.032

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.21

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