rs41302867

Variant names:

• chr6-7240643-G-A
• rs41302867
• NM_001003699.4:c.3973+41G>A

Variant summary

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

The NM_001003699.4(RREB1):​c.3973+41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,584,576 control chromosomes in the GnomAD database, including 9,944 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 0.082 (687 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9257 hom.)
• Consequence: RREB1 NM_001003699.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.951
• Publications: 14 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 = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RREB1	NM_001003699.4	c.3973+41G>A		intron_variant	Intron 11 of 12	ENST00000379938.7	NP_001003699.1
RREB1	NM_001003698.4	c.3809-5781G>A		intron_variant	Intron 10 of 11		NP_001003698.1
RREB1	NM_001168344.2	c.3809-5781G>A		intron_variant	Intron 10 of 11		NP_001161816.1
RREB1	NM_001003700.2	c.3973+41G>A		intron_variant	Intron 11 of 11		NP_001003700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RREB1	ENST00000379938.7	c.3973+41G>A		intron_variant	Intron 11 of 12	1	NM_001003699.4	ENSP00000369270.2
RREB1	ENST00000349384.10	c.3809-5781G>A		intron_variant	Intron 10 of 11	1		ENSP00000305560.10
RREB1	ENST00000379933.7	c.3809-5781G>A		intron_variant	Intron 10 of 11	1		ENSP00000369265.3
RREB1	ENST00000334984.10	c.3973+41G>A		intron_variant	Intron 11 of 11	1		ENSP00000335574.6

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 12451 AN: 152152 Hom.: 687 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0919

Gnomad ASJ AF: 0.0815

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0443

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.0969

GnomAD2 exomes AF: 0.0849 AC: 20280 AN: 238992 AF XY: 0.0874

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.0647

Gnomad ASJ exome AF: 0.0753

Gnomad EAS exome AF: 0.000338

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.0976

GnomAD4 exome AF: 0.108 AC: 154909 AN: 1432306 Hom.: 9257 Cov.: 25 AF XY: 0.107 AC XY: 75913 AN XY: 711040

African (AFR) AF: 0.0183 AC: 594 AN: 32544

American (AMR) AF: 0.0695 AC: 2944 AN: 42378

Ashkenazi Jewish (ASJ) AF: 0.0747 AC: 1910 AN: 25556

East Asian (EAS) AF: 0.000357 AC: 14 AN: 39184

South Asian (SAS) AF: 0.0455 AC: 3818 AN: 83838

European-Finnish (FIN) AF: 0.107 AC: 5660 AN: 52716

Middle Eastern (MID) AF: 0.0861 AC: 488 AN: 5668

European-Non Finnish (NFE) AF: 0.122 AC: 133547 AN: 1091336

Other (OTH) AF: 0.100 AC: 5934 AN: 59086

GnomAD4 genome AF: 0.0817 AC: 12448 AN: 152270 Hom.: 687 Cov.: 32 AF XY: 0.0802 AC XY: 5975 AN XY: 74460

African (AFR) AF: 0.0220 AC: 916 AN: 41554

American (AMR) AF: 0.0918 AC: 1404 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0815 AC: 283 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5182

South Asian (SAS) AF: 0.0448 AC: 216 AN: 4826

European-Finnish (FIN) AF: 0.104 AC: 1100 AN: 10606

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8195 AN: 68014

Other (OTH) AF: 0.0955 AC: 202 AN: 2116

Alfa AF: 0.0942 Hom.: 291

Bravo AF: 0.0805

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.7
DANN	Benign	0.63
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41302867; hg19: chr6-7240876;