6-7181922-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001003699.4(RREB1):c.11G>A(p.Ser4Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000678 in 1,614,252 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (5 hom.)
• Consequence: RREB1 NM_001003699.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.860

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006005436).
• BP6: Variant 6-7181922-G-A is Benign according to our data. Variant chr6-7181922-G-A is described in ClinVar as [Benign]. Clinvar id is 791534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 417 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RREB1	NM_001003699.4	c.11G>A	p.Ser4Asn	missense_variant	4/13	ENST00000379938.7
RREB1	NM_001003698.4	c.11G>A	p.Ser4Asn	missense_variant	4/12
RREB1	NM_001168344.2	c.11G>A	p.Ser4Asn	missense_variant	4/12
RREB1	NM_001003700.2	c.11G>A	p.Ser4Asn	missense_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RREB1	ENST00000379938.7	c.11G>A	p.Ser4Asn	missense_variant	4/13	1	NM_001003699.4	P1

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 417 AN: 152252 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00943

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000808 AC: 203 AN: 251368 Hom.: 0 AF XY: 0.000670 AC XY: 91 AN XY: 135852

Gnomad AFR exome AF: 0.00954

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: 0.000462 AC: 675 AN: 1461882 Hom.: 5 Cov.: 31 AF XY: 0.000441 AC XY: 321 AN XY: 727244

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.000693

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: 0.00126

GnomAD4 genome AF: 0.00276 AC: 420 AN: 152370 Hom.: 2 Cov.: 32 AF XY: 0.00264 AC XY: 197 AN XY: 74510

Gnomad4 AFR AF: 0.00947

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000473 Hom.: 1

Bravo AF: 0.00311

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00107 AC: 130

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RREB1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 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

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	17
Dann	Benign	0.93
DEOGEN2	Benign	0.010	T;T;.;.;.;.;T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.21	N
MetaRNN	Benign	0.0030	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.46	N;.;N;.;.;N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.35	N;N;N;N;D;N;N;N
REVEL	Benign	0.019
Sift	Benign	0.19	T;T;T;T;.;T;T;T
Sift4G	Benign	0.18	T;T;T;T;.;T;T;T
Polyphen		0.0030	B;.;B;.;.;B;B;.
Vest4		0.28
MVP		0.15
MPC		0.53
ClinPred		0.0014	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.026
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs116821447; hg19: chr6-7182155;