1-63774569-C-T

Variant names:

• chr1-63774569-C-T
• rs606550
• NM_005012.4:c.91+61C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005012.4(ROR1):​c.91+61C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 907,782 control chromosomes in the GnomAD database, including 33,321 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (11207 hom., cov: 29)
  • Exomes 𝑓: 0.23 (22114 hom.)
• Consequence: ROR1 NM_005012.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.574
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-63774569-C-T is Benign according to our data. Variant chr1-63774569-C-T is described in ClinVar as Benign. ClinVar VariationId is 1268836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.636 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.91+61C>T		intron	N/A	NP_005003.2
	ROR1	NM_001083592.2		c.91+61C>T		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.91+61C>T		intron	N/A	ENSP00000360120.1
	ROR1	ENST00000371080.5	TSL:1	c.91+61C>T		intron	N/A	ENSP00000360121.1

Frequencies

GnomAD3 genomes AF: 0.339 AC: 49962 AN: 147588 Hom.: 11153 Cov.: 29

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.299

GnomAD4 exome AF: 0.228 AC: 172945 AN: 760084 Hom.: 22114 AF XY: 0.228 AC XY: 81762 AN XY: 358290

African (AFR) AF: 0.689 AC: 9952 AN: 14452

American (AMR) AF: 0.207 AC: 572 AN: 2762

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 1521 AN: 6050

East Asian (EAS) AF: 0.163 AC: 1040 AN: 6366

South Asian (SAS) AF: 0.350 AC: 5307 AN: 15176

European-Finnish (FIN) AF: 0.191 AC: 1322 AN: 6922

Middle Eastern (MID) AF: 0.264 AC: 459 AN: 1740

European-Non Finnish (NFE) AF: 0.215 AC: 146009 AN: 679930

Other (OTH) AF: 0.253 AC: 6763 AN: 26686

GnomAD4 genome AF: 0.339 AC: 50081 AN: 147698 Hom.: 11207 Cov.: 29 AF XY: 0.337 AC XY: 24205 AN XY: 71926

African (AFR) AF: 0.642 AC: 26190 AN: 40786

American (AMR) AF: 0.219 AC: 3273 AN: 14958

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 882 AN: 3396

East Asian (EAS) AF: 0.177 AC: 881 AN: 4984

South Asian (SAS) AF: 0.352 AC: 1684 AN: 4780

European-Finnish (FIN) AF: 0.198 AC: 1837 AN: 9260

Middle Eastern (MID) AF: 0.223 AC: 65 AN: 292

European-Non Finnish (NFE) AF: 0.219 AC: 14502 AN: 66288

Other (OTH) AF: 0.308 AC: 633 AN: 2054

Alfa AF: 0.287 Hom.: 1013

Bravo AF: 0.347

Asia WGS AF: 0.298 AC: 892 AN: 3000

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.4
DANN	Benign	0.90
PhyloP100		-0.57
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: rs606550; hg19: chr1-64240240;