rs4960294

Variant names:

• chr6-7198740-A-C
• rs4960294
• NM_001003699.4:c.425+9418A>C

Variant summary

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

The NM_001003699.4(RREB1):​c.425+9418A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 152,078 control chromosomes in the GnomAD database, including 8,966 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 0.34 (8966 hom., cov: 32)
• Consequence: RREB1 NM_001003699.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 4 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):

• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.382 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RREB1	NM_001003699.4	MANE Select	c.425+9418A>C		intron	N/A	NP_001003699.1
	RREB1	NM_001003698.4		c.425+9418A>C		intron	N/A	NP_001003698.1
	RREB1	NM_001168344.2		c.425+9418A>C		intron	N/A	NP_001161816.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RREB1	ENST00000379938.7	TSL:1 MANE Select	c.425+9418A>C		intron	N/A	ENSP00000369270.2
	RREB1	ENST00000349384.10	TSL:1	c.425+9418A>C		intron	N/A	ENSP00000305560.10
	RREB1	ENST00000379933.7	TSL:1	c.425+9418A>C		intron	N/A	ENSP00000369265.3

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51500 AN: 151960 Hom.: 8966 Cov.: 32

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.365

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

GnomAD4 genome AF: 0.339 AC: 51502 AN: 152078 Hom.: 8966 Cov.: 32 AF XY: 0.336 AC XY: 24973 AN XY: 74350

African (AFR) AF: 0.288 AC: 11966 AN: 41478

American (AMR) AF: 0.319 AC: 4870 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1353 AN: 3466

East Asian (EAS) AF: 0.258 AC: 1335 AN: 5184

South Asian (SAS) AF: 0.220 AC: 1062 AN: 4824

European-Finnish (FIN) AF: 0.342 AC: 3618 AN: 10570

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26198 AN: 67960

Other (OTH) AF: 0.360 AC: 762 AN: 2114

Alfa AF: 0.359 Hom.: 2738

Bravo AF: 0.339

Asia WGS AF: 0.228 AC: 792 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.18
DANN	Benign	0.72
PhyloP100		-1.0
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: rs4960294; hg19: chr6-7198973;