1-64049734-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005012.4(ROR1):c.207G>A(p.Thr69=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,613,958 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (17 hom.)
• Consequence: ROR1 NM_005012.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.31

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 1-64049734-G-A is Benign according to our data. Variant chr1-64049734-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1574543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.31 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROR1	NM_005012.4	c.207G>A	p.Thr69=	synonymous_variant	3/9	ENST00000371079.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROR1	ENST00000371079.6	c.207G>A	p.Thr69=	synonymous_variant	3/9	1	NM_005012.4	P1
ROR1	ENST00000371080.5	c.207G>A	p.Thr69=	synonymous_variant	3/7	1
ROR1	ENST00000482426.1	n.241G>A		non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes AF: 0.00324 AC: 493 AN: 152066 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00537

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.00235 AC: 589 AN: 251060 Hom.: 5 AF XY: 0.00236 AC XY: 320 AN XY: 135722

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000879

Gnomad NFE exome AF: 0.00454

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00443 AC: 6474 AN: 1461774 Hom.: 17 Cov.: 35 AF XY: 0.00422 AC XY: 3066 AN XY: 727204

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.00556

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00324 AC: 493 AN: 152184 Hom.: 3 Cov.: 32 AF XY: 0.00293 AC XY: 218 AN XY: 74424

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.00537

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.00308 Hom.: 1

Bravo AF: 0.00313

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00367

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	ROR1: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	1.8
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs55806972; hg19: chr1-64515406;