rs11208305

Variant names:

• chr1-63849808-G-C
• rs11208305
• NM_005012.4:c.91+75300G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005012.4(ROR1):​c.91+75300G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 152,110 control chromosomes in the GnomAD database, including 3,630 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (3630 hom., cov: 33)
• Consequence: ROR1 NM_005012.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.603
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR1	NM_005012.4	c.91+75300G>C		intron_variant	Intron 1 of 8	ENST00000371079.6	NP_005003.2
ROR1	XM_011541526.2	c.-41783G>C		5_prime_UTR_variant	Exon 1 of 9		XP_011539828.1
ROR1	NM_001083592.2	c.91+75300G>C		intron_variant	Intron 1 of 6		NP_001077061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROR1	ENST00000371079.6	c.91+75300G>C		intron_variant	Intron 1 of 8	1	NM_005012.4	ENSP00000360120.1
ROR1	ENST00000371080.5	c.91+75300G>C		intron_variant	Intron 1 of 6	1		ENSP00000360121.1
ROR1	ENST00000482426.1	n.125+74394G>C		intron_variant	Intron 1 of 5	5

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32245 AN: 151992 Hom.: 3623 Cov.: 33

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.0473

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.207

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.212 AC: 32267 AN: 152110 Hom.: 3630 Cov.: 33 AF XY: 0.212 AC XY: 15779 AN XY: 74332

African (AFR) AF: 0.174 AC: 7214 AN: 41512

American (AMR) AF: 0.177 AC: 2712 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 694 AN: 3468

East Asian (EAS) AF: 0.0476 AC: 247 AN: 5188

South Asian (SAS) AF: 0.201 AC: 959 AN: 4780

European-Finnish (FIN) AF: 0.272 AC: 2867 AN: 10554

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16899 AN: 67990

Other (OTH) AF: 0.205 AC: 433 AN: 2112

Alfa AF: 0.226 Hom.: 466

Bravo AF: 0.203

Asia WGS AF: 0.131 AC: 459 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.5
DANN	Benign	0.64
PhyloP100		0.60
Mutation Taster		=100/0	polymorphism (auto)

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: rs11208305; hg19: chr1-64315479;