1-63774394-G-A

Variant names:

• chr1-63774394-G-A
• rs552545525
• NM_005012.4:c.-24G>A

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.-24G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,255,210 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (103 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (55 hom.)
• Consequence: ROR1 NM_005012.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.724
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-63774394-G-A is Benign according to our data. Variant chr1-63774394-G-A is described in ClinVar as Benign. ClinVar VariationId is 1235539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0661 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.-24G>A		5_prime_UTR	Exon 1 of 9	NP_005003.2
	ROR1	NM_001083592.2		c.-24G>A		5_prime_UTR	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.-24G>A		5_prime_UTR	Exon 1 of 9	ENSP00000360120.1
	ROR1	ENST00000371080.5	TSL:1	c.-24G>A		5_prime_UTR	Exon 1 of 7	ENSP00000360121.1

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2977 AN: 151280 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.0684

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00652

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000251

Gnomad OTH AF: 0.0145

GnomAD2 exomes AF: 0.00148 AC: 44 AN: 29784 AF XY: 0.00133

Gnomad AFR exome AF: 0.0659

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000830

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00166 AC: 1832 AN: 1103822 Hom.: 55 Cov.: 23 AF XY: 0.00147 AC XY: 789 AN XY: 538230

African (AFR) AF: 0.0687 AC: 1473 AN: 21426

American (AMR) AF: 0.00415 AC: 49 AN: 11814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14604

East Asian (EAS) AF: 0.00 AC: 0 AN: 19444

South Asian (SAS) AF: 0.000113 AC: 5 AN: 44332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21572

Middle Eastern (MID) AF: 0.00245 AC: 7 AN: 2852

European-Non Finnish (NFE) AF: 0.000130 AC: 120 AN: 925712

Other (OTH) AF: 0.00423 AC: 178 AN: 42066

GnomAD4 genome AF: 0.0197 AC: 2978 AN: 151388 Hom.: 103 Cov.: 32 AF XY: 0.0189 AC XY: 1400 AN XY: 73984

African (AFR) AF: 0.0682 AC: 2828 AN: 41452

American (AMR) AF: 0.00651 AC: 99 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10384

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000251 AC: 17 AN: 67624

Other (OTH) AF: 0.0143 AC: 30 AN: 2096

Alfa AF: 0.0170 Hom.: 12

Bravo AF: 0.0224

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	-0.52
CADD	Benign	13
DANN	Benign	0.96
PhyloP100		0.72
PromoterAI		0.020	Neutral
Mutation Taster		=299/1	polymorphism

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: rs552545525; hg19: chr1-64240065;