6-7189279-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001003699.4(RREB1):c.382A>G(p.Thr128Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,603,956 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000098 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: RREB1 NM_001003699.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010990143).
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RREB1	NM_001003699.4	c.382A>G	p.Thr128Ala	missense_variant	6/13	ENST00000379938.7
RREB1	NM_001003698.4	c.382A>G	p.Thr128Ala	missense_variant	6/12
RREB1	NM_001168344.2	c.382A>G	p.Thr128Ala	missense_variant	6/12
RREB1	NM_001003700.2	c.382A>G	p.Thr128Ala	missense_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RREB1	ENST00000379938.7	c.382A>G	p.Thr128Ala	missense_variant	6/13	1	NM_001003699.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000212 AC: 49 AN: 231136 Hom.: 0 AF XY: 0.000289 AC XY: 36 AN XY: 124720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000309

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 165 AN: 1451628 Hom.: 0 Cov.: 30 AF XY: 0.000153 AC XY: 110 AN XY: 721292

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000232

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.00156

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000154

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The c.382A>G (p.T128A) alteration is located in exon 6 (coding exon 3) of the RREB1 gene. This alteration results from a A to G substitution at nucleotide position 382, causing the threonine (T) at amino acid position 128 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.017	T;T;.;.;.;T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.22	N
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.011	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.70	N;.;N;.;N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N
REVEL	Benign	0.030
Sift	Benign	0.10	T;T;T;T;T;T;T
Sift4G	Uncertain	0.015	D;T;D;T;T;D;T
Polyphen		0.79	P;.;B;.;B;P;.
Vest4		0.27
MutPred		0.32		Loss of disorder (P = 0.1349);Loss of disorder (P = 0.1349);Loss of disorder (P = 0.1349);Loss of disorder (P = 0.1349);Loss of disorder (P = 0.1349);Loss of disorder (P = 0.1349);Loss of disorder (P = 0.1349);
MVP		0.57
MPC		0.57
ClinPred		0.032	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.068
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs568581314; hg19: chr6-7189512;