rs116821447

Variant names:

• chr6-7181922-G-A
• rs116821447
• NM_001003699.4:c.11G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-7181922-G-A
• chr6-7181922-G-C

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.860
• 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 -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/Likely_benign. ClinVar VariationId is 791534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 420 AD gene.

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.11G>A	p.Ser4Asn	missense	Exon 4 of 13	NP_001003699.1	Q92766-2
	RREB1	NM_001003698.4		c.11G>A	p.Ser4Asn	missense	Exon 4 of 12	NP_001003698.1	Q92766-1
	RREB1	NM_001168344.2		c.11G>A	p.Ser4Asn	missense	Exon 4 of 12	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.11G>A	p.Ser4Asn	missense	Exon 4 of 13	ENSP00000369270.2	Q92766-2
	RREB1	ENST00000349384.10	TSL:1	c.11G>A	p.Ser4Asn	missense	Exon 4 of 12	ENSP00000305560.10	Q92766-1
	RREB1	ENST00000379933.7	TSL:1	c.11G>A	p.Ser4Asn	missense	Exon 4 of 12	ENSP00000369265.3	Q92766-1

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

GnomAD2 exomes AF: 0.000808 AC: 203 AN: 251368 AF XY: 0.000670

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 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

African (AFR) AF: 0.0110 AC: 367 AN: 33478

American (AMR) AF: 0.000693 AC: 31 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.000149 AC: 166 AN: 1112002

Other (OTH) AF: 0.00126 AC: 76 AN: 60396

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

African (AFR) AF: 0.00947 AC: 394 AN: 41598

American (AMR) AF: 0.000980 AC: 15 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000953 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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	RREB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.46	N
PhyloP100		0.86
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.019
Sift	Benign	0.19	T
Sift4G	Benign	0.18	T
Polyphen		0.0030	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
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs116821447; hg19: chr6-7182155;