1-64049683-G-T

Variant names:

• chr1-64049683-G-T
• rs201785225
• NM_005012.4:c.164-8G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_005012.4(ROR1):​c.164-8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000365 in 1,610,714 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00061 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: ROR1 NM_005012.4 splice_region, intron
• Scores: Splicing: ADA: 0.0003171
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.258
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-64049683-G-T is Benign according to our data. Variant chr1-64049683-G-T is described in ClinVar as Benign. ClinVar VariationId is 1599733.Status of the report is criteria_provided_single_submitter, 1 stars.

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.164-8G>T		splice_region intron	N/A	NP_005003.2
	ROR1	NM_001083592.2		c.164-8G>T		splice_region intron	N/A	NP_001077061.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR1	ENST00000371079.6	TSL:1 MANE Select	c.164-8G>T		splice_region intron	N/A	ENSP00000360120.1
	ROR1	ENST00000371080.5	TSL:1	c.164-8G>T		splice_region intron	N/A	ENSP00000360121.1
	ROR1	ENST00000482426.1	TSL:5	n.198-8G>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000612 AC: 93 AN: 152054 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00671

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000571 AC: 142 AN: 248574 AF XY: 0.000595

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00456

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000339 AC: 495 AN: 1458542 Hom.: 0 Cov.: 29 AF XY: 0.000342 AC XY: 248 AN XY: 725080

African (AFR) AF: 0.0000299 AC: 1 AN: 33442

American (AMR) AF: 0.000112 AC: 5 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.000360 AC: 31 AN: 86078

European-Finnish (FIN) AF: 0.00434 AC: 229 AN: 52758

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5754

European-Non Finnish (NFE) AF: 0.000180 AC: 200 AN: 1109816

Other (OTH) AF: 0.000348 AC: 21 AN: 60284

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152172 Hom.: 1 Cov.: 32 AF XY: 0.000887 AC XY: 66 AN XY: 74380

African (AFR) AF: 0.0000241 AC: 1 AN: 41502

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00671 AC: 71 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68014

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000128

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.1
DANN	Benign	0.68
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.028
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: rs201785225; hg19: chr1-64515355;