13-49549530-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_018191.4(RCBTB1):​c.973C>G​(p.His325Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. H325Y) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

RCBTB1
NM_018191.4 missense

Scores

2
6
11

Clinical Significance

Not reported in ClinVar

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-49549530-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RCBTB1NM_018191.4 linkc.973C>G p.His325Asp 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
RCBTB1ENST00000378302.7 linkc.973C>G p.His325Asp missense_variant Exon 9 of 13 1 NM_018191.4 ENSP00000367552.2 Q8NDN9-1
RCBTB1ENST00000258646.3 linkc.973C>G p.His325Asp missense_variant Exon 7 of 11 2 ENSP00000258646.3 Q8NDN9-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
37
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.058
T;T
Eigen
Benign
0.13
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
1.0
.;D
M_CAP
Benign
0.014
T
MetaRNN
Uncertain
0.67
D;D
MetaSVM
Benign
-0.97
T
MutationAssessor
Uncertain
2.3
M;M
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-1.8
N;N
REVEL
Benign
0.23
Sift
Benign
0.95
T;T
Sift4G
Benign
0.82
T;T
Polyphen
0.61
P;P
Vest4
0.74
MutPred
0.47
Gain of catalytic residue at L320 (P = 0.0013);Gain of catalytic residue at L320 (P = 0.0013);
MVP
0.51
MPC
0.27
ClinPred
0.73
D
GERP RS
4.3
Varity_R
0.26
gMVP
0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-50123666; API