chr1-63774471-C-T

Variant names:

• chr1-63774471-C-T
• rs1404702316
• NM_005012.4:c.54C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_005012.4(ROR1):​c.54C>T​(p.Ala18Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000394 in 1,015,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000039 (0 hom.)
• Consequence: ROR1 NM_005012.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.622
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-63774471-C-T is Benign according to our data. Variant chr1-63774471-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2975684.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.622 with no splicing effect.

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.54C>T	p.Ala18Ala	synonymous	Exon 1 of 9	NP_005003.2	Q01973-1
	ROR1	NM_001083592.2		c.54C>T	p.Ala18Ala	synonymous	Exon 1 of 7	NP_001077061.1	Q01973-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR1	ENST00000371079.6	TSL:1 MANE Select	c.54C>T	p.Ala18Ala	synonymous	Exon 1 of 9	ENSP00000360120.1	Q01973-1
	ROR1	ENST00000371080.5	TSL:1	c.54C>T	p.Ala18Ala	synonymous	Exon 1 of 7	ENSP00000360121.1	Q01973-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000394 AC: 4 AN: 1015128 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 483472

African (AFR) AF: 0.00 AC: 0 AN: 20184

American (AMR) AF: 0.00 AC: 0 AN: 5842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10700

East Asian (EAS) AF: 0.0000555 AC: 1 AN: 18004

South Asian (SAS) AF: 0.00 AC: 0 AN: 20342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2522

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 882994

Other (OTH) AF: 0.0000784 AC: 3 AN: 38254

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

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	-0.43
CADD	Benign	12
DANN	Benign	0.94
PhyloP100		-0.62
PromoterAI		-0.045	Neutral
Mutation Taster		=100/0	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: rs1404702316; hg19: chr1-64240142;