chr1-63774424-C-T

Variant names:

• chr1-63774424-C-T
• NM_005012.4:c.7C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005012.4(ROR1):​c.7C>T​(p.Arg3Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R3R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.7e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ROR1 NM_005012.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.385
• Publications: 0 publications found

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]

ROR1 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive 108

  Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18091571).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005012.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR1	NM_005012.4	MANE Select	c.7C>T	p.Arg3Trp	missense	Exon 1 of 9	NP_005003.2
	ROR1	NM_001083592.2		c.7C>T	p.Arg3Trp	missense	Exon 1 of 7	NP_001077061.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR1	ENST00000371079.6	TSL:1 MANE Select	c.7C>T	p.Arg3Trp	missense	Exon 1 of 9	ENSP00000360120.1
	ROR1	ENST00000371080.5	TSL:1	c.7C>T	p.Arg3Trp	missense	Exon 1 of 7	ENSP00000360121.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.72e-7 AC: 1 AN: 1028774 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 490670

African (AFR) AF: 0.00 AC: 0 AN: 20418

American (AMR) AF: 0.00 AC: 0 AN: 6106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11112

East Asian (EAS) AF: 0.00 AC: 0 AN: 19276

South Asian (SAS) AF: 0.00 AC: 0 AN: 21142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2572

European-Non Finnish (NFE) AF: 0.00000112 AC: 1 AN: 891750

Other (OTH) AF: 0.00 AC: 0 AN: 39068

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.39
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.17
MutPred		0.27		Loss of methylation at R5 (P = 0.0188)
MVP		0.35
MPC		0.45
ClinPred		0.35	T
GERP RS		1.1
PromoterAI		0.018	Neutral
Varity_R		0.16
gMVP		0.59
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

hg19: chr1-64240095;