6-7187481-G-T

Variant names:

• chr6-7187481-G-T
• rs1765142540
• NM_001003699.4:c.219G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001003699.4(RREB1):​c.219G>T​(p.Lys73Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RREB1 NM_001003699.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

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]

Y_RNA (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RREB1	NM_001003699.4	c.219G>T	p.Lys73Asn	missense_variant	Exon 5 of 13	ENST00000379938.7	NP_001003699.1
RREB1	NM_001003698.4	c.219G>T	p.Lys73Asn	missense_variant	Exon 5 of 12		NP_001003698.1
RREB1	NM_001168344.2	c.219G>T	p.Lys73Asn	missense_variant	Exon 5 of 12		NP_001161816.1
RREB1	NM_001003700.2	c.219G>T	p.Lys73Asn	missense_variant	Exon 5 of 12		NP_001003700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RREB1	ENST00000379938.7	c.219G>T	p.Lys73Asn	missense_variant	Exon 5 of 13	1	NM_001003699.4	ENSP00000369270.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453934 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 723478

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: 0.00

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.219G>T (p.K73N) alteration is located in exon 5 (coding exon 2) of the RREB1 gene. This alteration results from a G to T substitution at nucleotide position 219, causing the lysine (K) at amino acid position 73 to be replaced by an asparagine (N). 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	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.;.;.;T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	.;T;T;T;T;T;T
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.2	M;.;M;.;M;M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0030	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;D;.
Vest4		0.62
MutPred		0.51		Loss of methylation at K73 (P = 8e-04);Loss of methylation at K73 (P = 8e-04);Loss of methylation at K73 (P = 8e-04);Loss of methylation at K73 (P = 8e-04);Loss of methylation at K73 (P = 8e-04);Loss of methylation at K73 (P = 8e-04);Loss of methylation at K73 (P = 8e-04);
MVP		0.85
MPC		0.99
ClinPred		0.95	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.67
gMVP		0.73

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: rs1765142540; hg19: chr6-7187714;