6-7189185-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001003699.4(RREB1):​c.288C>A​(p.Asp96Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D96D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

RREB1
NM_001003699.4 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.84
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.37087804).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RREB1NM_001003699.4 linkc.288C>A p.Asp96Glu missense_variant Exon 6 of 13 ENST00000379938.7 NP_001003699.1 Q92766-2
RREB1NM_001003698.4 linkc.288C>A p.Asp96Glu missense_variant Exon 6 of 12 NP_001003698.1 Q92766-1A0A024QZU8
RREB1NM_001168344.2 linkc.288C>A p.Asp96Glu missense_variant Exon 6 of 12 NP_001161816.1 Q92766-1A0A024QZU8
RREB1NM_001003700.2 linkc.288C>A p.Asp96Glu missense_variant Exon 6 of 12 NP_001003700.1 Q92766-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RREB1ENST00000379938.7 linkc.288C>A p.Asp96Glu missense_variant Exon 6 of 13 1 NM_001003699.4 ENSP00000369270.2 Q92766-2

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152216
Hom.:
0
Cov.:
32
FAILED QC
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461192
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726896
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
152216
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74372
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 20, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.288C>A (p.D96E) alteration is located in exon 6 (coding exon 3) of the RREB1 gene. This alteration results from a C to A substitution at nucleotide position 288, causing the aspartic acid (D) at amino acid position 96 to be replaced by a glutamic acid (E). 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
Uncertain
0.50
BayesDel_addAF
Uncertain
0.018
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.051
T;T;.;.;.;T;T
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.71
.;T;T;T;T;T;T
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.37
T;T;T;T;T;T;T
MetaSVM
Benign
-0.63
T
MutationAssessor
Benign
0.66
N;.;N;.;N;N;.
PrimateAI
Pathogenic
0.80
D
PROVEAN
Uncertain
-2.5
N;D;N;N;N;N;D
REVEL
Benign
0.21
Sift
Uncertain
0.016
D;T;D;T;D;D;D
Sift4G
Benign
0.14
T;T;T;T;T;T;T
Polyphen
0.99
D;.;D;.;D;D;.
Vest4
0.65
MutPred
0.34
Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);
MVP
0.63
MPC
1.4
ClinPred
0.98
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.33
gMVP
0.37

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: chr6-7189418; API