6-7189165-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001003699.4(RREB1):c.268A>G(p.Thr90Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,612,772 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (12 hom.)
• Consequence: RREB1 NM_001003699.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.88

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076525807).
• BP6: Variant 6-7189165-A-G is Benign according to our data. Variant chr6-7189165-A-G is described in ClinVar as [Benign]. Clinvar id is 768060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7189165-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00802 (1222/152296) while in subpopulation AFR AF= 0.0281 (1168/41552). AF 95% confidence interval is 0.0268. There are 13 homozygotes in gnomad4. There are 572 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1220 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RREB1	NM_001003699.4	c.268A>G	p.Thr90Ala	missense_variant	6/13	ENST00000379938.7
RREB1	NM_001003698.4	c.268A>G	p.Thr90Ala	missense_variant	6/12
RREB1	NM_001168344.2	c.268A>G	p.Thr90Ala	missense_variant	6/12
RREB1	NM_001003700.2	c.268A>G	p.Thr90Ala	missense_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RREB1	ENST00000379938.7	c.268A>G	p.Thr90Ala	missense_variant	6/13	1	NM_001003699.4	P1

Frequencies

GnomAD3 genomes AF: 0.00802 AC: 1220 AN: 152178 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00227 AC: 566 AN: 249310 Hom.: 4 AF XY: 0.00159 AC XY: 214 AN XY: 134802

Gnomad AFR exome AF: 0.0291

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.000889 AC: 1299 AN: 1460476 Hom.: 12 Cov.: 30 AF XY: 0.000780 AC XY: 567 AN XY: 726542

Gnomad4 AFR exome AF: 0.0289

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000382

Gnomad4 NFE exome AF: 0.0000818

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00802 AC: 1222 AN: 152296 Hom.: 13 Cov.: 32 AF XY: 0.00768 AC XY: 572 AN XY: 74472

Gnomad4 AFR AF: 0.0281

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00117 Hom.: 2

Bravo AF: 0.00911

ESP6500AA AF: 0.0281 AC: 124

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00273 AC: 331

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RREB1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.036	T;T;.;.;.;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0077	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.93	L;.;L;.;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D
REVEL	Benign	0.10
Sift	Benign	0.062	T;T;T;T;T;T;T
Sift4G	Pathogenic	0.0	D;T;D;T;D;D;D
Polyphen		0.99	D;.;P;.;D;D;.
Vest4		0.22
MVP		0.44
MPC		0.72
ClinPred		0.032	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.21

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: rs73374662; hg19: chr6-7189398;