rs9379084

Positions:

• chr6-7231610-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.092 (797 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10655 hom.)
• Consequence: RREB1 NM_001003699.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 9.33

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 1297809.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-7231610-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
RREB1	NM_001003699.4	c.3511G>A	p.Asp1171Asn	missense_variant	10/13	ENST00000379938.7	NP_001003699.1
RREB1	NM_001003698.4	c.3511G>A	p.Asp1171Asn	missense_variant	10/12		NP_001003698.1
RREB1	NM_001168344.2	c.3511G>A	p.Asp1171Asn	missense_variant	10/12		NP_001161816.1
RREB1	NM_001003700.2	c.3511G>A	p.Asp1171Asn	missense_variant	10/12		NP_001003700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RREB1	ENST00000379938.7	c.3511G>A	p.Asp1171Asn	missense_variant	10/13	1	NM_001003699.4	ENSP00000369270.2
RREB1	ENST00000349384.10	c.3511G>A	p.Asp1171Asn	missense_variant	10/12	1		ENSP00000305560.10
RREB1	ENST00000379933.7	c.3511G>A	p.Asp1171Asn	missense_variant	10/12	1		ENSP00000369265.3
RREB1	ENST00000334984.10	c.3511G>A	p.Asp1171Asn	missense_variant	10/12	1		ENSP00000335574.6

Frequencies

GnomAD3 genomes AF: 0.0919 AC: 13976 AN: 152090 Hom.: 797 Cov.: 32

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

GnomAD3 exomes AF: 0.106 AC: 25472 AN: 241000 Hom.: 1509 AF XY: 0.111 AC XY: 14662 AN XY: 132390

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 SAS exome AF: 0.114

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.: 37 AF XY: 0.117 AC XY: 85230 AN XY: 725852

Gnomad4 AFR exome AF: 0.0198

Gnomad4 AMR exome AF: 0.0746

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.203

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.118

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.0918 AC: 13976 AN: 152208 Hom.: 797 Cov.: 32 AF XY: 0.0929 AC XY: 6912 AN XY: 74430

Gnomad4 AFR AF: 0.0249

Gnomad4 AMR AF: 0.0967

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.103

Alfa AF: 0.114 Hom.: 1348

Bravo AF: 0.0884

TwinsUK AF: 0.111 AC: 412

ALSPAC AF: 0.112 AC: 433

ESP6500AA AF: 0.0221 AC: 96

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

Submissions by phenotype

RREB1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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

GeneDx

Apr 09, 2021

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	T
BayesDel_noAF	Benign	-0.56
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;.;.;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D;D;D
MetaRNN	Benign	0.0028	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M;M;M;.
PrimateAI	Uncertain	0.57	T
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	T
GERP RS		5.7
Varity_R		0.25
gMVP		0.28

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: rs9379084; hg19: chr6-7231843; COSMIC: COSV58553827; COSMIC: COSV58553827;