chr1-64177967-C-T

Position:

• chr1-64177967-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000371079.6(ROR1):​c.1926C>T​(p.Ser642=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 1,614,136 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (156 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (146 hom.)
• Consequence: ROR1 ENST00000371079.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.01

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 1-64177967-C-T is Benign according to our data. Variant chr1-64177967-C-T is described in ClinVar as [Benign]. Clinvar id is 586410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROR1	NM_005012.4	c.1926C>T	p.Ser642=	synonymous_variant	9/9	ENST00000371079.6	NP_005003.2
ROR1	XM_017001376.2	c.1866C>T	p.Ser622=	synonymous_variant	8/8		XP_016856865.1
ROR1	XM_011541526.2	c.1737C>T	p.Ser579=	synonymous_variant	9/9		XP_011539828.1
ROR1	XM_017001377.2	c.1737C>T	p.Ser579=	synonymous_variant	10/10		XP_016856866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROR1	ENST00000371079.6	c.1926C>T	p.Ser642=	synonymous_variant	9/9	1	NM_005012.4	ENSP00000360120	P1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3763 AN: 152132 Hom.: 156 Cov.: 32

Gnomad AFR AF: 0.0856

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.00683 AC: 1713 AN: 250666 Hom.: 53 AF XY: 0.00495 AC XY: 671 AN XY: 135442

Gnomad AFR exome AF: 0.0900

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000372

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00269 AC: 3939 AN: 1461886 Hom.: 146 Cov.: 34 AF XY: 0.00225 AC XY: 1638 AN XY: 727242

Gnomad4 AFR exome AF: 0.0914

Gnomad4 AMR exome AF: 0.00503

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000178

Gnomad4 OTH exome AF: 0.00580

GnomAD4 genome AF: 0.0248 AC: 3779 AN: 152250 Hom.: 156 Cov.: 32 AF XY: 0.0252 AC XY: 1880 AN XY: 74466

Gnomad4 AFR AF: 0.0857

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0165

Alfa AF: 0.0119 Hom.: 29

Bravo AF: 0.0279

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -

ROR1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.2
DANN	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs35586842; hg19: chr1-64643650;