chr13-49549573-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5

The NM_018191.4(RCBTB1):c.930G>T(p.Trp310Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RCBTB1
NM_018191.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.57

Publications

5 publications found

Variant links:

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

RCBTB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a repeat RCC1 6 (size 52) in uniprot entity RCBT1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_018191.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

PP5

Variant 13-49549573-C-A is Pathogenic according to our data. Variant chr13-49549573-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 253017.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCBTB1	NM_018191.4 link	c.930G>T	p.Trp310Cys	missense_variant	Exon 9 of 13	ENST00000378302.7	NP_060661.3	Q8NDN9-1B3KR20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCBTB1	ENST00000378302.7 link	c.930G>T	p.Trp310Cys	missense_variant	Exon 9 of 13	1	NM_018191.4	ENSP00000367552.2		Q8NDN9-1
RCBTB1	ENST00000258646.3 link	c.930G>T	p.Trp310Cys	missense_variant	Exon 7 of 11	2		ENSP00000258646.3		Q8NDN9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251162

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111992

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Oct 11, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tryptophan with cysteine at codon 310 of the RCBTB1 protein (p.Trp310Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is present in population databases (rs772592456, ExAC 0.002%). This missense change has been observed in individual(s) with inherited retinal disease (PMID: 27486781). ClinVar contains an entry for this variant (Variation ID: 253017). 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 disruptive. 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. -

Sep 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RETINAL DYSTROPHY WITH EXTRAOCULAR ANOMALIES

Pathogenic:1

Nov 01, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Retinitis pigmentosa

Pathogenic:1

Center for Medical Genetics Ghent, University of Ghent

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;T

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

.;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Pathogenic

2.9

M;M

PhyloP100

7.6

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-12

D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.98

MutPred

0.69

Gain of catalytic residue at G305 (P = 0.0026);Gain of catalytic residue at G305 (P = 0.0026);

MVP

0.98

MPC

0.97

ClinPred

1.0

GERP RS

5.2

Varity_R

0.96

gMVP

0.98

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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chr13-49549573-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over