1-63774431-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005012.4(ROR1):c.14G>T(p.Arg5Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,027,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ROR1 NM_005012.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ROR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.2330701).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROR1	NM_005012.4	c.14G>T	p.Arg5Leu	missense_variant	1/9	ENST00000371079.6
ROR1	NM_001083592.2	c.14G>T	p.Arg5Leu	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROR1	ENST00000371079.6	c.14G>T	p.Arg5Leu	missense_variant	1/9	1	NM_005012.4	P1
ROR1	ENST00000371080.5	c.14G>T	p.Arg5Leu	missense_variant	1/7	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000224 AC: 23 AN: 1027358 Hom.: 0 Cov.: 30 AF XY: 0.0000245 AC XY: 12 AN XY: 489592

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000258

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.14G>T (p.R5L) alteration is located in exon 1 (coding exon 1) of the ROR1 gene. This alteration results from a G to T substitution at nucleotide position 14, causing the arginine (R) at amino acid position 5 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	23
Dann	Uncertain	0.98
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.51	T;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.99	N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	0.070	N;N
REVEL	Benign	0.093
Sift	Benign	0.26	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.0	.;B
Vest4		0.29
MutPred		0.22		Loss of methylation at R5 (P = 0.0121);Loss of methylation at R5 (P = 0.0121);
MVP		0.57
MPC		0.54
ClinPred		0.31	T
GERP RS		3.2
Varity_R		0.16
gMVP		0.57

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: chr1-64240102;