rs2139103335

Variant names:

• chr13-49534164-T-A
• rs2139103335
• NM_018191.4:c.1554A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018191.4(RCBTB1):​c.1554A>T​(p.Glu518Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RCBTB1 NM_018191.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.453
• Publications: 0 publications found

Genes affected

RCBTB1 (HGNC:18243): (RCC1 and BTB domain containing protein 1) This gene encodes a protein with an N-terminal RCC1 domain and a C-terminal BTB (broad complex, tramtrack and bric-a-brac) domain. In rat, over-expression of this gene in vascular smooth muscle cells induced cellular hypertrophy. In rat, the C-terminus of RCBTB1 interacts with the angiotensin II receptor-1A. In humans, this gene maps to a region of chromosome 13q that is frequently deleted in B-cell chronic lymphocytic leukemia and other lymphoid malignancies. [provided by RefSeq, Jul 2008]

RCBTB1 Gene-Disease associations (from GenCC):

• RCBTB1-related retinopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• reticular dystrophy of the retinal pigment epithelium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• exudative vitreoretinopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036062866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCBTB1	NM_018191.4	c.1554A>T	p.Glu518Asp	missense_variant	Exon 13 of 13	ENST00000378302.7	NP_060661.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCBTB1	ENST00000378302.7	c.1554A>T	p.Glu518Asp	missense_variant	Exon 13 of 13	1	NM_018191.4	ENSP00000367552.2
RCBTB1	ENST00000258646.3	c.1554A>T	p.Glu518Asp	missense_variant	Exon 11 of 11	2		ENSP00000258646.3
RCBTB1	ENST00000471984.1	n.442A>T		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with RCBTB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 518 of the RCBTB1 protein (p.Glu518Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.037	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.036	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.11	N;N
PhyloP100		-0.45
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.080	N;N
REVEL	Benign	0.15
Sift	Benign	0.58	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0010	B;B
Vest4		0.085
MutPred		0.46		Gain of catalytic residue at F519 (P = 0.0127);Gain of catalytic residue at F519 (P = 0.0127);
MVP		0.17
MPC		0.17
ClinPred		0.086	T
GERP RS		-1.1
Varity_R		0.061
gMVP		0.38
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs2139103335; hg19: chr13-50108300;