6-7240344-A-T

Variant names:

• chr6-7240344-A-T
• rs2714337
• NM_001003699.4:c.3809-94A>T

Variant summary

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

The NM_001003699.4(RREB1):​c.3809-94A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 922,630 control chromosomes in the GnomAD database, including 54,438 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 (8868 hom., cov: 30)
  • Exomes 𝑓: 0.34 (45570 hom.)
• Consequence: RREB1 NM_001003699.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0400
• Publications: 18 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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RREB1	NM_001003699.4	c.3809-94A>T		intron_variant	Intron 10 of 12	ENST00000379938.7	NP_001003699.1
RREB1	NM_001003698.4	c.3809-6080A>T		intron_variant	Intron 10 of 11		NP_001003698.1
RREB1	NM_001168344.2	c.3809-6080A>T		intron_variant	Intron 10 of 11		NP_001161816.1
RREB1	NM_001003700.2	c.3809-94A>T		intron_variant	Intron 10 of 11		NP_001003700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RREB1	ENST00000379938.7	c.3809-94A>T		intron_variant	Intron 10 of 12	1	NM_001003699.4	ENSP00000369270.2
RREB1	ENST00000349384.10	c.3809-6080A>T		intron_variant	Intron 10 of 11	1		ENSP00000305560.10
RREB1	ENST00000379933.7	c.3809-6080A>T		intron_variant	Intron 10 of 11	1		ENSP00000369265.3
RREB1	ENST00000334984.10	c.3809-94A>T		intron_variant	Intron 10 of 11	1		ENSP00000335574.6

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51033 AN: 151488 Hom.: 8870 Cov.: 30

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.319

GnomAD4 exome AF: 0.337 AC: 260115 AN: 771026 Hom.: 45570 AF XY: 0.338 AC XY: 132234 AN XY: 390676

African (AFR) AF: 0.282 AC: 5205 AN: 18464

American (AMR) AF: 0.419 AC: 9535 AN: 22770

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 4743 AN: 15184

East Asian (EAS) AF: 0.229 AC: 7424 AN: 32450

South Asian (SAS) AF: 0.357 AC: 13723 AN: 38446

European-Finnish (FIN) AF: 0.398 AC: 16350 AN: 41092

Middle Eastern (MID) AF: 0.343 AC: 1265 AN: 3684

European-Non Finnish (NFE) AF: 0.337 AC: 190305 AN: 564166

Other (OTH) AF: 0.333 AC: 11565 AN: 34770

GnomAD4 genome AF: 0.337 AC: 51048 AN: 151604 Hom.: 8868 Cov.: 30 AF XY: 0.341 AC XY: 25229 AN XY: 74080

African (AFR) AF: 0.291 AC: 12021 AN: 41324

American (AMR) AF: 0.373 AC: 5688 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1126 AN: 3464

East Asian (EAS) AF: 0.347 AC: 1793 AN: 5160

South Asian (SAS) AF: 0.386 AC: 1856 AN: 4814

European-Finnish (FIN) AF: 0.410 AC: 4278 AN: 10422

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.344 AC: 23338 AN: 67884

Other (OTH) AF: 0.319 AC: 670 AN: 2102

Alfa AF: 0.330 Hom.: 1071

Bravo AF: 0.332

Asia WGS AF: 0.406 AC: 1409 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.76
PhyloP100		-0.040
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: rs2714337; hg19: chr6-7240577; COSMIC: COSV107409749;