1-64009249-A-G

Variant names:

• chr1-64009249-A-G
• rs12091083
• NM_005012.4:c.92-56A>G

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.92-56A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00605 in 1,308,252 control chromosomes in the GnomAD database, including 419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (254 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (165 hom.)
• Consequence: ROR1 NM_005012.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.662
• Publications: 1 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=-0.89).
• BP6: Variant 1-64009249-A-G is Benign according to our data. Variant chr1-64009249-A-G is described in ClinVar as Benign. ClinVar VariationId is 1260821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 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.92-56A>G		intron	N/A	NP_005003.2
	ROR1	NM_001083592.2		c.92-56A>G		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.92-56A>G		intron	N/A	ENSP00000360120.1
	ROR1	ENST00000371080.5	TSL:1	c.92-56A>G		intron	N/A	ENSP00000360121.1
	ROR1	ENST00000482426.1	TSL:5	n.126-56A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4519 AN: 151966 Hom.: 254 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00806

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.00293 AC: 3382 AN: 1156168 Hom.: 165 AF XY: 0.00248 AC XY: 1465 AN XY: 590856

African (AFR) AF: 0.104 AC: 2834 AN: 27316

American (AMR) AF: 0.00387 AC: 171 AN: 44236

Ashkenazi Jewish (ASJ) AF: 0.0000415 AC: 1 AN: 24094

East Asian (EAS) AF: 0.00 AC: 0 AN: 38244

South Asian (SAS) AF: 0.000213 AC: 17 AN: 79846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.00371 AC: 19 AN: 5124

European-Non Finnish (NFE) AF: 0.0000516 AC: 43 AN: 833980

Other (OTH) AF: 0.00593 AC: 297 AN: 50102

GnomAD4 genome AF: 0.0298 AC: 4530 AN: 152084 Hom.: 254 Cov.: 32 AF XY: 0.0288 AC XY: 2142 AN XY: 74358

African (AFR) AF: 0.105 AC: 4351 AN: 41466

American (AMR) AF: 0.00805 AC: 123 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68000

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.0317 Hom.: 23

Bravo AF: 0.0325

Asia WGS AF: 0.00982 AC: 35 AN: 3478

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	-0.89
CADD	Benign	7.4
DANN	Benign	0.60
PhyloP100		0.66
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: rs12091083; hg19: chr1-64474921;