chr1-64009338-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_005012.4(ROR1):c.125C>G(p.Pro42Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P42L) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
ROR1
NM_005012.4 missense
NM_005012.4 missense
Scores
3
7
8
Clinical Significance
Conservation
PhyloP100: 5.11
Genes affected
ROR1 (HGNC:10256): (receptor tyrosine kinase like orphan receptor 1) This gene encodes a receptor tyrosine kinase-like orphan receptor that modulates neurite growth in the central nervous system. The encoded protein is a glycosylated type I membrane protein that belongs to the ROR subfamily of cell surface receptors. It is a pseudokinase that lacks catalytic activity and may interact with the non-canonical Wnt signalling pathway. This gene is highly expressed during early embryonic development but expressed at very low levels in adult tissues. Increased expression of this gene is associated with B-cell chronic lymphocytic leukaemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, ROR1
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ROR1 | NM_005012.4 | c.125C>G | p.Pro42Arg | missense_variant | 2/9 | ENST00000371079.6 | |
ROR1 | NM_001083592.2 | c.125C>G | p.Pro42Arg | missense_variant | 2/7 | ||
ROR1 | XM_011541526.2 | c.-65C>G | 5_prime_UTR_variant | 2/9 | |||
ROR1 | XM_017001377.2 | c.-161C>G | 5_prime_UTR_variant | 1/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ROR1 | ENST00000371079.6 | c.125C>G | p.Pro42Arg | missense_variant | 2/9 | 1 | NM_005012.4 | P1 | |
ROR1 | ENST00000371080.5 | c.125C>G | p.Pro42Arg | missense_variant | 2/7 | 1 | |||
ROR1 | ENST00000482426.1 | n.159C>G | non_coding_transcript_exon_variant | 2/6 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152146Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461516Hom.: 0 Cov.: 29 AF XY: 0.00000963 AC XY: 7AN XY: 727100
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 18, 2021 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ROR1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 42 of the ROR1 protein (p.Pro42Arg). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and arginine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;N
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;T
Sift4G
Benign
T;T
Polyphen
1.0
.;D
Vest4
MutPred
Gain of phosphorylation at S45 (P = 0.0828);Gain of phosphorylation at S45 (P = 0.0828);
MVP
MPC
0.50
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at