Genetic Variant RCBTB1:p.Asp486Val (chr13-49534261-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018191.4(RCBTB1):c.1457A>T(p.Asp486Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D486G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RCBTB1
NM_018191.4 missense, splice_region

Scores

Splicing: ADA: 0.9110

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.67

Publications

0 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: 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

RCBTB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RCBTB1	NM_018191.4	MANE Select	c.1457A>T	p.Asp486Val	missense splice_region	Exon 13 of 13	NP_060661.3
RCBTB1	NM_001352500.2		c.1457A>T	p.Asp486Val	missense splice_region	Exon 13 of 13	NP_001339429.1	Q8NDN9-1
RCBTB1	NM_001352501.2		c.1457A>T	p.Asp486Val	missense splice_region	Exon 12 of 12	NP_001339430.1	Q8NDN9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RCBTB1	ENST00000378302.7	TSL:1 MANE Select	c.1457A>T	p.Asp486Val	missense splice_region	Exon 13 of 13	ENSP00000367552.2	Q8NDN9-1
RCBTB1	ENST00000258646.3	TSL:2	c.1457A>T	p.Asp486Val	missense splice_region	Exon 11 of 11	ENSP00000258646.3	Q8NDN9-1
RCBTB1	ENST00000860932.1		c.1457A>T	p.Asp486Val	missense splice_region	Exon 12 of 12	ENSP00000530991.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000405

AC:

AN:

246698

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:

0.00000899

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.099

MetaRNN

Uncertain

0.70

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.3

PhyloP100

7.7

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.74

MutPred

0.48

Gain of catalytic residue at E488 (P = 0.044)

MVP

0.64

MPC

0.64

ClinPred

0.99

GERP RS

5.7

Varity_R

0.73

gMVP

0.80

Mutation Taster

=34/66

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.91

dbscSNV1_RF

Pathogenic

0.79

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over