rs557074

Variant names:

• chr6-7144958-T-G
• rs557074
• NM_001003699.4:c.-284-31697T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001003699.4(RREB1):​c.-284-31697T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 152,104 control chromosomes in the GnomAD database, including 6,606 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (6606 hom., cov: 32)
• Consequence: RREB1 NM_001003699.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.307
• Publications: 9 publications found

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):

• RASopathy

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia
• 22q11.2 deletion syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003699.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RREB1	NM_001003699.4	MANE Select	c.-284-31697T>G		intron	N/A	NP_001003699.1	Q92766-2
	RREB1	NM_001003698.4		c.-284-31697T>G		intron	N/A	NP_001003698.1	Q92766-1
	RREB1	NM_001168344.2		c.-284-31697T>G		intron	N/A	NP_001161816.1	Q92766-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RREB1	ENST00000379938.7	TSL:1 MANE Select	c.-284-31697T>G		intron	N/A	ENSP00000369270.2	Q92766-2
	RREB1	ENST00000349384.10	TSL:1	c.-284-31697T>G		intron	N/A	ENSP00000305560.10	Q92766-1
	RREB1	ENST00000379933.7	TSL:1	c.-284-31697T>G		intron	N/A	ENSP00000369265.3	Q92766-1

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39704 AN: 151986 Hom.: 6586 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.0627

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.229

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.261 AC: 39770 AN: 152104 Hom.: 6606 Cov.: 32 AF XY: 0.255 AC XY: 18929 AN XY: 74358

African (AFR) AF: 0.471 AC: 19532 AN: 41446

American (AMR) AF: 0.169 AC: 2588 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 747 AN: 3468

East Asian (EAS) AF: 0.0627 AC: 325 AN: 5184

South Asian (SAS) AF: 0.113 AC: 545 AN: 4824

European-Finnish (FIN) AF: 0.190 AC: 2010 AN: 10588

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.196 AC: 13291 AN: 67984

Other (OTH) AF: 0.226 AC: 478 AN: 2114

Alfa AF: 0.212 Hom.: 1907

Bravo AF: 0.271

Asia WGS AF: 0.122 AC: 424 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.58
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs557074; hg19: chr6-7145191;