chr6-7189267-C-G

Variant names:

• chr6-7189267-C-G
• NM_001003699.4:c.370C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.33

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 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	c.370C>G	p.Pro124Ala	missense_variant	Exon 6 of 13	ENST00000379938.7	NP_001003699.1
RREB1	NM_001003698.4	c.370C>G	p.Pro124Ala	missense_variant	Exon 6 of 12		NP_001003698.1
RREB1	NM_001168344.2	c.370C>G	p.Pro124Ala	missense_variant	Exon 6 of 12		NP_001161816.1
RREB1	NM_001003700.2	c.370C>G	p.Pro124Ala	missense_variant	Exon 6 of 12		NP_001003700.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455038 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723282

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.: 32

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	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
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	D
LIST_S2	Uncertain	0.92	.;D;D;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.6	M;.;M;.;M;M;.
PrimateAI	Pathogenic	0.89	D
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	D
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.

Other links and lift over

hg19: chr6-7189500;