rs1173539126

Variant names:

• chr1-63774451-C-G
• rs1173539126
• NM_005012.4:c.34C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-63774451-C-G
• chr1-63774451-C-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.34C>G​(p.Pro12Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000017 in 1,175,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 9.8e-7 (0 hom.)
• Consequence: ROR1 NM_005012.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250
• 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: AR, Unknown Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=0.117382735).

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.34C>G	p.Pro12Ala	missense	Exon 1 of 9	NP_005003.2	Q01973-1
	ROR1	NM_001083592.2		c.34C>G	p.Pro12Ala	missense	Exon 1 of 7	NP_001077061.1	Q01973-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR1	ENST00000371079.6	TSL:1 MANE Select	c.34C>G	p.Pro12Ala	missense	Exon 1 of 9	ENSP00000360120.1	Q01973-1
	ROR1	ENST00000371080.5	TSL:1	c.34C>G	p.Pro12Ala	missense	Exon 1 of 7	ENSP00000360121.1	Q01973-3

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149916 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: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.75e-7 AC: 1 AN: 1025150 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 488272

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

African (AFR) AF: 0.00 AC: 0 AN: 20444

American (AMR) AF: 0.00 AC: 0 AN: 6056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11054

East Asian (EAS) AF: 0.00 AC: 0 AN: 19232

South Asian (SAS) AF: 0.00 AC: 0 AN: 20390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2558

European-Non Finnish (NFE) AF: 0.00000112 AC: 1 AN: 889390

Other (OTH) AF: 0.00 AC: 0 AN: 38846

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149916 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73104

African (AFR) AF: 0.00 AC: 0 AN: 41208

American (AMR) AF: 0.00 AC: 0 AN: 15062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9826

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

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67154

Other (OTH) AF: 0.00 AC: 0 AN: 2062

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.69
DEOGEN2	Benign	0.085	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.025
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.072
Sift	Benign	0.34	T
Sift4G	Uncertain	0.060	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.29		Loss of glycosylation at P12 (P = 0.0119)
MVP		0.38
MPC		0.42
ClinPred		0.036	T
GERP RS		1.8
PromoterAI		-0.044	Neutral
Varity_R		0.048
gMVP		0.39
Mutation Taster		=71/29	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: rs1173539126; hg19: chr1-64240122;