6-7181925-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001003699.4(RREB1):c.14C>G(p.Ser5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S5L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RREB1 NM_001003699.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.741

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23989758).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RREB1	NM_001003699.4	c.14C>G	p.Ser5Trp	missense_variant	4/13	ENST00000379938.7
RREB1	NM_001003698.4	c.14C>G	p.Ser5Trp	missense_variant	4/12
RREB1	NM_001168344.2	c.14C>G	p.Ser5Trp	missense_variant	4/12
RREB1	NM_001003700.2	c.14C>G	p.Ser5Trp	missense_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RREB1	ENST00000379938.7	c.14C>G	p.Ser5Trp	missense_variant	4/13	1	NM_001003699.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Nov 03, 2023

The c.14C>G (p.S5W) alteration is located in exon 4 (coding exon 1) of the RREB1 gene. This alteration results from a C to G substitution at nucleotide position 14, causing the serine (S) at amino acid position 5 to be replaced by a tryptophan (W). 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	0.24
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;.;.;.;T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.64	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.24	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;L;.;L;L;.
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;D;.
Vest4		0.49
MutPred		0.34		Loss of phosphorylation at T5 (P = 0.0098);Loss of phosphorylation at T5 (P = 0.0098);Loss of phosphorylation at T5 (P = 0.0098);Loss of phosphorylation at T5 (P = 0.0098);Loss of phosphorylation at T5 (P = 0.0098);Loss of phosphorylation at T5 (P = 0.0098);Loss of phosphorylation at T5 (P = 0.0098);
MVP		0.33
MPC		1.7
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.093
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-7182158;