1-63774491-G-A

Variant names:

• chr1-63774491-G-A
• rs1644599905
• NM_005012.4:c.74G>A

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.74G>A​(p.Arg25His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000175 in 1,145,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: ROR1 NM_005012.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0240
• 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=0.17705965).

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.74G>A	p.Arg25His	missense	Exon 1 of 9	NP_005003.2
	ROR1	NM_001083592.2		c.74G>A	p.Arg25His	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.74G>A	p.Arg25His	missense	Exon 1 of 9	ENSP00000360120.1
	ROR1	ENST00000371080.5	TSL:1	c.74G>A	p.Arg25His	missense	Exon 1 of 7	ENSP00000360121.1

Frequencies

GnomAD3 genomes AF: 0.00000671 AC: 1 AN: 149058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000100 AC: 1 AN: 996530 Hom.: 0 Cov.: 30 AF XY: 0.00000211 AC XY: 1 AN XY: 474774

African (AFR) AF: 0.00 AC: 0 AN: 19700

American (AMR) AF: 0.00 AC: 0 AN: 5760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10084

East Asian (EAS) AF: 0.00 AC: 0 AN: 15584

South Asian (SAS) AF: 0.00 AC: 0 AN: 20704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2460

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 870444

Other (OTH) AF: 0.0000270 AC: 1 AN: 37000

GnomAD4 genome AF: 0.00000671 AC: 1 AN: 149058 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72636

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41078

American (AMR) AF: 0.00 AC: 0 AN: 15000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66786

Other (OTH) AF: 0.00 AC: 0 AN: 2054

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.024
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.084
Sift	Benign	0.57	T
Sift4G	Benign	0.19	T
Polyphen		0.50	P
Vest4		0.097
MutPred		0.34		Loss of methylation at R25 (P = 0.0268)
MVP		0.62
MPC		0.54
ClinPred		0.28	T
GERP RS		3.7
PromoterAI		0.073	Neutral
Varity_R		0.072
gMVP		0.24
Mutation Taster		=79/21	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

dbSNP: rs1644599905; hg19: chr1-64240162;