NM_005012.4:c.52_63dupGCCGCGCTGCTG

Variant names:

• chr1-63774459-G-GGCGCTGCTGGCC
• rs1182541863
• NM_005012.4:c.52_63dupGCCGCGCTGCTG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_005012.4(ROR1):​c.52_63dupGCCGCGCTGCTG​(p.Ala18_Leu21dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,171,218 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: ROR1 NM_005012.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.189
• 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 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005012.4.

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.52_63dupGCCGCGCTGCTG	p.Ala18_Leu21dup	conservative_inframe_insertion	Exon 1 of 9	NP_005003.2
	ROR1	NM_001083592.2		c.52_63dupGCCGCGCTGCTG	p.Ala18_Leu21dup	conservative_inframe_insertion	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.52_63dupGCCGCGCTGCTG	p.Ala18_Leu21dup	conservative_inframe_insertion	Exon 1 of 9	ENSP00000360120.1
	ROR1	ENST00000371080.5	TSL:1	c.52_63dupGCCGCGCTGCTG	p.Ala18_Leu21dup	conservative_inframe_insertion	Exon 1 of 7	ENSP00000360121.1

Frequencies

GnomAD3 genomes AF: 0.0000601 AC: 9 AN: 149700 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: 0.000134

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 582 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000305 AC: 312 AN: 1021518 Hom.: 0 Cov.: 30 AF XY: 0.000310 AC XY: 151 AN XY: 486612

African (AFR) AF: 0.0000492 AC: 1 AN: 20332

American (AMR) AF: 0.00 AC: 0 AN: 5978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10904

East Asian (EAS) AF: 0.00 AC: 0 AN: 18822

South Asian (SAS) AF: 0.00 AC: 0 AN: 20404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2548

European-Non Finnish (NFE) AF: 0.000342 AC: 303 AN: 887074

Other (OTH) AF: 0.000207 AC: 8 AN: 38594

GnomAD4 genome AF: 0.0000601 AC: 9 AN: 149700 Hom.: 0 Cov.: 32 AF XY: 0.0000822 AC XY: 6 AN XY: 73002

African (AFR) AF: 0.00 AC: 0 AN: 41180

American (AMR) AF: 0.00 AC: 0 AN: 15056

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: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000134 AC: 9 AN: 67072

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

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.19
Mutation Taster		=80/20	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1182541863; hg19: chr1-64240130;