1-64049895-C-T

Variant names:

• chr1-64049895-C-T
• NM_005012.4:c.368C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005012.4(ROR1):​c.368C>T​(p.Thr123Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ROR1 NM_005012.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR1	NM_005012.4	c.368C>T	p.Thr123Ile	missense_variant	Exon 3 of 9	ENST00000371079.6	NP_005003.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROR1	ENST00000371079.6	c.368C>T	p.Thr123Ile	missense_variant	Exon 3 of 9	1	NM_005012.4	ENSP00000360120.1
ROR1	ENST00000371080.5	c.368C>T	p.Thr123Ile	missense_variant	Exon 3 of 7	1		ENSP00000360121.1
ROR1	ENST00000482426.1	n.402C>T		non_coding_transcript_exon_variant	Exon 3 of 6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with ROR1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 123 of the ROR1 protein (p.Thr123Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.0	D;N;.
REVEL	Uncertain	0.31
Sift	Benign	0.061	T;D;.
Sift4G	Uncertain	0.0070	D;T;T
Polyphen		0.34	.;B;.
Vest4		0.74
MutPred		0.53		Loss of catalytic residue at T123 (P = 0.0219);Loss of catalytic residue at T123 (P = 0.0219);.;
MVP		0.49
MPC		1.3
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.20
gMVP		0.60

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: chr1-64515567;