6-7181930-G-A

Variant names:

• chr6-7181930-G-A
• rs367922483
• NM_001003699.4:c.19G>A

Variant summary

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

The NM_001003699.4(RREB1):​c.19G>A​(p.Ala7Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000681 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: RREB1 NM_001003699.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.121

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=0.017352253).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RREB1	NM_001003699.4	c.19G>A	p.Ala7Thr	missense_variant	Exon 4 of 13	ENST00000379938.7	NP_001003699.1
RREB1	NM_001003698.4	c.19G>A	p.Ala7Thr	missense_variant	Exon 4 of 12		NP_001003698.1
RREB1	NM_001168344.2	c.19G>A	p.Ala7Thr	missense_variant	Exon 4 of 12		NP_001161816.1
RREB1	NM_001003700.2	c.19G>A	p.Ala7Thr	missense_variant	Exon 4 of 12		NP_001003700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RREB1	ENST00000379938.7	c.19G>A	p.Ala7Thr	missense_variant	Exon 4 of 13	1	NM_001003699.4	ENSP00000369270.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251342 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

Gnomad4 AFR AF: 0.0000241

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.19G>A (p.A7T) alteration is located in exon 4 (coding exon 1) of the RREB1 gene. This alteration results from a G to A substitution at nucleotide position 19, causing the alanine (A) at amino acid position 7 to be replaced by a threonine (T). 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	0.069
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.82
DANN	Benign	0.84
DEOGEN2	Benign	0.0069	T;T;.;.;.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.12	.;T;T;T;T;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.017	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.2	N;.;N;.;N;N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.37	N;N;N;N;N;N;N
REVEL	Benign	0.055
Sift	Benign	0.56	T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0010	B;.;B;.;B;B;.
Vest4		0.13
MVP		0.27
MPC		0.51
ClinPred		0.024	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.033
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

LitVar

Other links and lift over

dbSNP: rs367922483; hg19: chr6-7182163; COSMIC: COSV58552989; COSMIC: COSV58552989;