1-64049707-C-T

Variant names:

• chr1-64049707-C-T
• rs1772626
• NM_005012.4:c.180C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005012.4(ROR1):​c.180C>T​(p.Leu60Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,613,364 control chromosomes in the GnomAD database, including 576,951 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (48726 hom., cov: 30)
  • Exomes 𝑓: 0.85 (528225 hom.)
• Consequence: ROR1 NM_005012.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -5.37
• Publications: 22 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-64049707-C-T is Benign according to our data. Variant chr1-64049707-C-T is described in ClinVar as Benign. ClinVar VariationId is 1240716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

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.180C>T	p.Leu60Leu	synonymous	Exon 3 of 9	NP_005003.2	Q01973-1
	ROR1	NM_001083592.2		c.180C>T	p.Leu60Leu	synonymous	Exon 3 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.180C>T	p.Leu60Leu	synonymous	Exon 3 of 9	ENSP00000360120.1	Q01973-1
	ROR1	ENST00000371080.5	TSL:1	c.180C>T	p.Leu60Leu	synonymous	Exon 3 of 7	ENSP00000360121.1	Q01973-3
	ROR1	ENST00000482426.1	TSL:5	n.214C>T		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes AF: 0.794 AC: 120668 AN: 151882 Hom.: 48692 Cov.: 30

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.838

Gnomad AMR AF: 0.848

Gnomad ASJ AF: 0.884

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.797

Gnomad FIN AF: 0.871

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.849

Gnomad OTH AF: 0.796

GnomAD2 exomes AF: 0.846 AC: 211561 AN: 250144 AF XY: 0.845

Gnomad AFR exome AF: 0.623

Gnomad AMR exome AF: 0.886

Gnomad ASJ exome AF: 0.876

Gnomad EAS exome AF: 0.958

Gnomad FIN exome AF: 0.876

Gnomad NFE exome AF: 0.851

Gnomad OTH exome AF: 0.832

GnomAD4 exome AF: 0.849 AC: 1240676 AN: 1461364 Hom.: 528225 Cov.: 52 AF XY: 0.848 AC XY: 616490 AN XY: 726968

African (AFR) AF: 0.621 AC: 20790 AN: 33466

American (AMR) AF: 0.879 AC: 39291 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 22940 AN: 26132

East Asian (EAS) AF: 0.963 AC: 38248 AN: 39698

South Asian (SAS) AF: 0.803 AC: 69259 AN: 86232

European-Finnish (FIN) AF: 0.876 AC: 46719 AN: 53310

Middle Eastern (MID) AF: 0.800 AC: 4616 AN: 5768

European-Non Finnish (NFE) AF: 0.853 AC: 948034 AN: 1111654

Other (OTH) AF: 0.841 AC: 50779 AN: 60380

GnomAD4 genome AF: 0.794 AC: 120757 AN: 152000 Hom.: 48726 Cov.: 30 AF XY: 0.798 AC XY: 59275 AN XY: 74290

African (AFR) AF: 0.637 AC: 26353 AN: 41402

American (AMR) AF: 0.848 AC: 12960 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.884 AC: 3065 AN: 3468

East Asian (EAS) AF: 0.958 AC: 4932 AN: 5148

South Asian (SAS) AF: 0.796 AC: 3816 AN: 4792

European-Finnish (FIN) AF: 0.871 AC: 9213 AN: 10582

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.849 AC: 57739 AN: 68002

Other (OTH) AF: 0.797 AC: 1684 AN: 2114

Alfa AF: 0.833 Hom.: 85735

Bravo AF: 0.788

Asia WGS AF: 0.852 AC: 2960 AN: 3478

EpiCase AF: 0.838

EpiControl AF: 0.838

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hearing loss, autosomal recessive 108 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.39
DANN	Benign	0.57
PhyloP100		-5.4
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: rs1772626; hg19: chr1-64515379; COSMIC: COSV64285163;