dbSNP rs1432619363: RREB1:p.Pro124Ala (chr6-7189267-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001003699.4(RREB1):c.370C>G(p.Pro124Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RREB1
NM_001003699.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.33

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]

RREB1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RREB1	NM_001003699.4 link	c.370C>G	p.Pro124Ala	missense_variant	Exon 6 of 13	ENST00000379938.7	NP_001003699.1	Q92766-2
RREB1	NM_001003698.4 link	c.370C>G	p.Pro124Ala	missense_variant	Exon 6 of 12		NP_001003698.1	Q92766-1A0A024QZU8
RREB1	NM_001168344.2 link	c.370C>G	p.Pro124Ala	missense_variant	Exon 6 of 12		NP_001161816.1	Q92766-1A0A024QZU8
RREB1	NM_001003700.2 link	c.370C>G	p.Pro124Ala	missense_variant	Exon 6 of 12		NP_001003700.1	Q92766-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RREB1	ENST00000379938.7 link	c.370C>G	p.Pro124Ala	missense_variant	Exon 6 of 13	1	NM_001003699.4	ENSP00000369270.2		Q92766-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455038

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723282

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;T;.;.;.;T;T

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D;D;D;D;D;D

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.76

D;D;D;D;D;D;D

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.6

M;.;M;.;M;M;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.2

D;D;D;D;D;D;D

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

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

0.86

MutPred

0.44

Gain of MoRF binding (P = 0.0769);Gain of MoRF binding (P = 0.0769);Gain of MoRF binding (P = 0.0769);Gain of MoRF binding (P = 0.0769);Gain of MoRF binding (P = 0.0769);Gain of MoRF binding (P = 0.0769);Gain of MoRF binding (P = 0.0769);

MVP

0.64

MPC

1.4

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.77

gMVP

0.60

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over