rs777630688

Positions:

• chr13-49552181-GT-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_018191.4(RCBTB1):​c.707del​(p.Asn236ThrfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,572,696 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: RCBTB1 NM_018191.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.71

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-49552181-GT-G is Pathogenic according to our data. Variant chr13-49552181-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 224622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-49552181-GT-G is described in Lovd as [Pathogenic]. Variant chr13-49552181-GT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RCBTB1	NM_018191.4	c.707del	p.Asn236ThrfsTer11	frameshift_variant	7/13	ENST00000378302.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RCBTB1	ENST00000378302.7	c.707del	p.Asn236ThrfsTer11	frameshift_variant	7/13	1	NM_018191.4	P1
RCBTB1	ENST00000258646.3	c.707del	p.Asn236ThrfsTer11	frameshift_variant	5/11	2		P1
RCBTB1	ENST00000490058.1	n.71del		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000113 AC: 22 AN: 194238 Hom.: 0 AF XY: 0.000106 AC XY: 11 AN XY: 103326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00146

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000155 AC: 22 AN: 1420592 Hom.: 0 Cov.: 28 AF XY: 0.0000156 AC XY: 11 AN XY: 703040

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000521

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000339

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 30 AF XY: 0.0000404 AC XY: 3 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RCBTB1-related retinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The homozygous variant is shared with the affected family members (3billion dataset). The variant has been reported to be associated with RCBTB1 related disorder (ClinVar ID: VCV000224622). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Exudative retinopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Laboratory of Human Molecular Genetics, Department of Medical Research, Taipei Veterans General Hospital

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not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 19, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 224622). This premature translational stop signal has been observed in individual(s) with Coats disease and retinal dystrophy (PMID: 26908610, 31494449). This variant is present in population databases (rs777630688, gnomAD 0.2%). This sequence change creates a premature translational stop signal (p.Asn236Thrfs*11) in the RCBTB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RCBTB1 are known to be pathogenic (PMID: 31494449). -

Computational scores

Source: dbNSFP v4.3

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: rs777630688; hg19: chr13-50126317;