chr1-64178248-G-C

Variant names:

• chr1-64178248-G-C
• rs1553163562
• NM_005012.4:c.2207G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005012.4(ROR1):​c.2207G>C​(p.Arg736Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as no classifications from unflagged records (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ROR1 NM_005012.4 missense
• Clinical Significance: no classifications from unflagged records no classifications from unflagged records P:1
• Conservation: PhyloP100: 9.60
• 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

ENSG00000303693 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR1	NM_005012.4	c.2207G>C	p.Arg736Thr	missense_variant	Exon 9 of 9	ENST00000371079.6	NP_005003.2
ROR1	XM_017001376.2	c.2147G>C	p.Arg716Thr	missense_variant	Exon 8 of 8		XP_016856865.1
ROR1	XM_011541526.2	c.2018G>C	p.Arg673Thr	missense_variant	Exon 9 of 9		XP_011539828.1
ROR1	XM_017001377.2	c.2018G>C	p.Arg673Thr	missense_variant	Exon 10 of 10		XP_016856866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROR1	ENST00000371079.6	c.2207G>C	p.Arg736Thr	missense_variant	Exon 9 of 9	1	NM_005012.4	ENSP00000360120.1
ENSG00000303693	ENST00000796579.1	n.580-4608C>G		intron_variant	Intron 5 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: no classifications from unflagged records

Submissions summary: Pathogenic:1

Revision: no classifications from unflagged records

Submissions by phenotype

Hearing loss, autosomal recessive 108 Pathogenic:1

Sep 13, 2017

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.
PhyloP100		9.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.0	D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.90		Gain of phosphorylation at R736 (P = 0.0174);.;
MVP		0.94
MPC		1.6
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.98
gMVP		0.98
Mutation Taster		=13/87	disease causing (ClinVar)

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

dbSNP: rs1553163562; hg19: chr1-64643931;