rs9379084

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001003699.4(RREB1):c.3511G>A(p.Asp1171Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,611,528 control chromosomes in the GnomAD database, including 11,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.092 ( 797 hom., cov: 32)

Exomes 𝑓: 0.12 ( 10655 hom. )

Consequence

RREB1
NM_001003699.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 9.33

Publications

81 publications found

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 Gene-Disease associations (from GenCC):

22q11.2 deletion syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RREB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027750134).

BP6

Variant 6-7231610-G-A is Benign according to our data. Variant chr6-7231610-G-A is described in ClinVar as Benign. ClinVar VariationId is 1297809.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RREB1	NM_001003699.4 link	c.3511G>A	p.Asp1171Asn	missense_variant	Exon 10 of 13	ENST00000379938.7	NP_001003699.1	Q92766-2
RREB1	NM_001003698.4 link	c.3511G>A	p.Asp1171Asn	missense_variant	Exon 10 of 12		NP_001003698.1	Q92766-1A0A024QZU8
RREB1	NM_001168344.2 link	c.3511G>A	p.Asp1171Asn	missense_variant	Exon 10 of 12		NP_001161816.1	Q92766-1A0A024QZU8
RREB1	NM_001003700.2 link	c.3511G>A	p.Asp1171Asn	missense_variant	Exon 10 of 12		NP_001003700.1	Q92766-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RREB1	ENST00000379938.7 link	c.3511G>A	p.Asp1171Asn	missense_variant	Exon 10 of 13	1	NM_001003699.4	ENSP00000369270.2	Q92766-2
RREB1	ENST00000349384.10 link	c.3511G>A	p.Asp1171Asn	missense_variant	Exon 10 of 12	1		ENSP00000305560.10	Q92766-1
RREB1	ENST00000379933.7 link	c.3511G>A	p.Asp1171Asn	missense_variant	Exon 10 of 12	1		ENSP00000369265.3	Q92766-1
RREB1	ENST00000334984.10 link	c.3511G>A	p.Asp1171Asn	missense_variant	Exon 10 of 12	1		ENSP00000335574.6	Q92766-3

Frequencies

GnomAD3 genomes

AF:

0.0919

AC:

13976

AN:

152090

Hom.:

797

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0250

Gnomad AMI

AF:

0.113

Gnomad AMR

AF:

0.0967

Gnomad ASJ

AF:

0.121

Gnomad EAS

AF:

0.156

Gnomad SAS

AF:

0.118

Gnomad FIN

AF:

0.112

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.119

Gnomad OTH

AF:

0.105

GnomAD2 exomes

AF:

0.106

AC:

25472

AN:

241000

AF XY:

0.111

show subpopulations

Gnomad AFR exome

AF:

0.0251

Gnomad AMR exome

AF:

0.0700

Gnomad ASJ exome

AF:

0.114

Gnomad EAS exome

AF:

0.132

Gnomad FIN exome

AF:

0.112

Gnomad NFE exome

AF:

0.118

Gnomad OTH exome

AF:

0.113

GnomAD4 exome

AF:

0.116

AC:

169984

AN:

1459320

Hom.:

10655

Cov.:

AF XY:

0.117

AC XY:

85230

AN XY:

725852

show subpopulations

African (AFR)

AF:

0.0198

AC:

663

AN:

33444

American (AMR)

AF:

0.0746

AC:

3327

AN:

44574

Ashkenazi Jewish (ASJ)

AF:

0.118

AC:

3077

AN:

26110

East Asian (EAS)

AF:

0.203

AC:

8058

AN:

39672

South Asian (SAS)

AF:

0.114

AC:

9818

AN:

86190

European-Finnish (FIN)

AF:

0.113

AC:

5889

AN:

52058

Middle Eastern (MID)

AF:

0.133

AC:

737

AN:

5544

European-Non Finnish (NFE)

AF:

0.118

AC:

131355

AN:

1111488

Other (OTH)

AF:

0.117

AC:

7060

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

8858

17716

26575

35433

44291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4686

9372

14058

18744

23430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0918

AC:

13976

AN:

152208

Hom.:

797

Cov.:

AF XY:

0.0929

AC XY:

6912

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0249

AC:

1034

AN:

41554

American (AMR)

AF:

0.0967

AC:

1479

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.121

AC:

419

AN:

3472

East Asian (EAS)

AF:

0.157

AC:

805

AN:

5142

South Asian (SAS)

AF:

0.119

AC:

572

AN:

4824

European-Finnish (FIN)

AF:

0.112

AC:

1187

AN:

10608

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.119

AC:

8106

AN:

67984

Other (OTH)

AF:

0.103

AC:

219

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

633

1266

1899

2532

3165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

166

332

498

664

830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.114

Hom.:

2981

Bravo

AF:

0.0884

TwinsUK

AF:

0.111

AC:

412

ALSPAC

AF:

0.112

AC:

433

ESP6500AA

AF:

0.0221

AC:

ESP6500EA

AF:

0.110

AC:

939

ExAC

AF:

0.100

AC:

12107

Asia WGS

AF:

0.104

AC:

359

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

RREB1-related disorder

Benign:1

Oct 17, 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

Apr 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27398621, 29632382, 30297969) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.10

T;.;.;T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D;D;D

MetaRNN

Benign

0.0028

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;M;M;M;.

PhyloP100

9.3

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.8

D;D;D;D;.

REVEL

Benign

0.15

Sift

Uncertain

0.0090

D;D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.65

MPC

0.28

ClinPred

0.019

GERP RS

5.7

Varity_R

0.25

gMVP

0.28

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over