13-49549530-G-A

Position:

chr13-49549530-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PP5_ModerateBP4

The ENST00000378302.7(RCBTB1):c.973C>T(p.His325Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. H325H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

RCBTB1
ENST00000378302.7 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:4

Conservation

PhyloP100: 7.75

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a repeat RCC1 6 (size 52) in uniprot entity RCBT1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in ENST00000378302.7

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-49549530-G-A is Pathogenic according to our data. Variant chr13-49549530-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 253018.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-49549530-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.36090845). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RCBTB1	NM_018191.4 linkuse as main transcript	c.973C>T	p.His325Tyr	missense_variant	9/13	ENST00000378302.7	NP_060661.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RCBTB1	ENST00000378302.7 linkuse as main transcript	c.973C>T	p.His325Tyr	missense_variant	9/13	1	NM_018191.4	ENSP00000367552	P1	Q8NDN9-1
RCBTB1	ENST00000258646.3 linkuse as main transcript	c.973C>T	p.His325Tyr	missense_variant	7/11	2		ENSP00000258646	P1	Q8NDN9-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

251126

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000876

AC:

128

AN:

1461822

Hom.:

Cov.:

AF XY:

0.0000990

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.0000773

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000151

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000195

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

RETINAL DYSTROPHY WITH EXTRAOCULAR ANOMALIES

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2016

- -

RCBTB1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 2024

The RCBTB1 c.973C>T variant is predicted to result in the amino acid substitution p.His325Tyr. This variant was reported to segregate with retinal dystrophy within a large family consistent with autosomal recessive inheritance (Coppieters et al 2016. PubMed ID: 27486781, Family F1). This variant is reported in 0.15% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 325 of the RCBTB1 protein (p.His325Tyr). This variant is present in population databases (rs200826424, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of retinal dystrophy (PMID: 27486781). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 253018). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RCBTB1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Center for Medical Genetics Ghent, University of Ghent

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.079

T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

.;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.36

T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.19

Sift

Benign

0.094

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.97

D;D

Vest4

0.66

MVP

0.57

MPC

0.47

ClinPred

0.27

GERP RS

4.3

Varity_R

0.24

gMVP

0.74

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over