6-7182047-C-T

Variant names:

• chr6-7182047-C-T
• rs141007836
• NM_001003699.4:c.136C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001003699.4(RREB1):​c.136C>T​(p.Pro46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,614,006 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: RREB1 NM_001003699.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.81
• Publications: 3 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048724413).
• BP6: Variant 6-7182047-C-T is Benign according to our data. Variant chr6-7182047-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 740171.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 194 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.136C>T	p.Pro46Ser	missense	Exon 4 of 13	NP_001003699.1	Q92766-2
	RREB1	NM_001003698.4		c.136C>T	p.Pro46Ser	missense	Exon 4 of 12	NP_001003698.1	Q92766-1
	RREB1	NM_001168344.2		c.136C>T	p.Pro46Ser	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.136C>T	p.Pro46Ser	missense	Exon 4 of 13	ENSP00000369270.2	Q92766-2
	RREB1	ENST00000349384.10	TSL:1	c.136C>T	p.Pro46Ser	missense	Exon 4 of 12	ENSP00000305560.10	Q92766-1
	RREB1	ENST00000379933.7	TSL:1	c.136C>T	p.Pro46Ser	missense	Exon 4 of 12	ENSP00000369265.3	Q92766-1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152034 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000366 AC: 92 AN: 251208 AF XY: 0.000287

Gnomad AFR exome AF: 0.00480

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000156 AC: 228 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.000116 AC XY: 84 AN XY: 727226

African (AFR) AF: 0.00436 AC: 146 AN: 33478

American (AMR) AF: 0.000201 AC: 9 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000549 AC: 61 AN: 1112002

Other (OTH) AF: 0.000182 AC: 11 AN: 60396

GnomAD4 genome AF: 0.00128 AC: 194 AN: 152152 Hom.: 2 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74392

African (AFR) AF: 0.00427 AC: 177 AN: 41490

American (AMR) AF: 0.000850 AC: 13 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67984

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000364 Hom.: 0

Bravo AF: 0.00136

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000412 AC: 50

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.77
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.8
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.045
Sift	Benign	0.54	T
Sift4G	Benign	0.66	T
Polyphen		0.076	B
Vest4		0.24
MVP		0.39
MPC		0.60
ClinPred		0.011	T
GERP RS		4.0
Varity_R		0.092
gMVP		0.38
Mutation Taster		=99/1	polymorphism

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: rs141007836; hg19: chr6-7182280; COSMIC: COSV99051005; COSMIC: COSV99051005;