rs368217569

Variant names:

• chr13-49549584-C-T
• rs368217569
• NM_018191.4:c.919G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_Moderate PP5

The NM_018191.4(RCBTB1):​c.919G>A​(p.Val307Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: RCBTB1 NM_018191.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 5.85
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics, 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: G2P, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 13-49549584-C-T is Pathogenic according to our data. Variant chr13-49549584-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 253016.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018191.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCBTB1	NM_018191.4	MANE Select	c.919G>A	p.Val307Met	missense	Exon 9 of 13	NP_060661.3
	RCBTB1	NM_001352500.2		c.919G>A	p.Val307Met	missense	Exon 9 of 13	NP_001339429.1	Q8NDN9-1
	RCBTB1	NM_001352501.2		c.919G>A	p.Val307Met	missense	Exon 8 of 12	NP_001339430.1	Q8NDN9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCBTB1	ENST00000378302.7	TSL:1 MANE Select	c.919G>A	p.Val307Met	missense	Exon 9 of 13	ENSP00000367552.2	Q8NDN9-1
	RCBTB1	ENST00000258646.3	TSL:2	c.919G>A	p.Val307Met	missense	Exon 7 of 11	ENSP00000258646.3	Q8NDN9-1
	RCBTB1	ENST00000860932.1		c.919G>A	p.Val307Met	missense	Exon 8 of 12	ENSP00000530991.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250914 AF XY: 0.00000738

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: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461796 Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5 AN XY: 727184

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	RCBTB1-related retinopathy (1)
1	-	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.90
MVP		0.90
MPC		0.72
ClinPred		0.91	D
GERP RS		5.2
Varity_R		0.50
gMVP		0.84
Mutation Taster		=28/72	disease causing (ClinVar)

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: rs368217569; hg19: chr13-50123720;