1-63774516-G-T

Variant names:

• chr1-63774516-G-T
• rs941042354
• NM_005012.4:c.91+8G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_005012.4(ROR1):​c.91+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,113,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: ROR1 NM_005012.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006795
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.00
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 1-63774516-G-T is Benign according to our data. Variant chr1-63774516-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1647648.Status of the report is criteria_provided_single_submitter, 1 stars.

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+8G>T		splice_region intron	N/A	NP_005003.2
	ROR1	NM_001083592.2		c.91+8G>T		splice_region 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+8G>T		splice_region intron	N/A	ENSP00000360120.1
	ROR1	ENST00000371080.5	TSL:1	c.91+8G>T		splice_region intron	N/A	ENSP00000360121.1

Frequencies

GnomAD3 genomes AF: 0.0000740 AC: 11 AN: 148620 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000135

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 1964 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000241 AC: 233 AN: 965242 Hom.: 0 Cov.: 26 AF XY: 0.000229 AC XY: 105 AN XY: 457776

African (AFR) AF: 0.0000527 AC: 1 AN: 18982

American (AMR) AF: 0.00 AC: 0 AN: 5110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9216

East Asian (EAS) AF: 0.00 AC: 0 AN: 12826

South Asian (SAS) AF: 0.00 AC: 0 AN: 20330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2326

European-Non Finnish (NFE) AF: 0.000270 AC: 229 AN: 848676

Other (OTH) AF: 0.0000854 AC: 3 AN: 35126

GnomAD4 genome AF: 0.0000740 AC: 11 AN: 148620 Hom.: 0 Cov.: 32 AF XY: 0.0000829 AC XY: 6 AN XY: 72356

African (AFR) AF: 0.00 AC: 0 AN: 41034

American (AMR) AF: 0.000134 AC: 2 AN: 14968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.000135 AC: 9 AN: 66586

Other (OTH) AF: 0.00 AC: 0 AN: 2044

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000110

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		3.0
PromoterAI		0.037	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000068
dbscSNV1_RF	Benign	0.0020
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: rs941042354; hg19: chr1-64240187;