chr1-64137385-G-T

Position:

• chr1-64137385-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000371079.6(ROR1):​c.499G>T​(p.Asp167Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ROR1 ENST00000371079.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.13

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-AS1 (HGNC:40508): (ROR1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ROR1. . Gene score misZ 2.1715 (greater than the threshold 3.09). Trascript score misZ 3.1383 (greater than threshold 3.09). GenCC has associacion of gene with nonsyndromic genetic hearing loss, hearing loss, autosomal recessive 108, hearing loss, autosomal recessive.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROR1	NM_005012.4	c.499G>T	p.Asp167Tyr	missense_variant	5/9	ENST00000371079.6	NP_005003.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROR1	ENST00000371079.6	c.499G>T	p.Asp167Tyr	missense_variant	5/9	1	NM_005012.4	ENSP00000360120	P1
ROR1-AS1	ENST00000424995.2	n.90-23594C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.499G>T (p.D167Y) alteration is located in exon 5 (coding exon 5) of the ROR1 gene. This alteration results from a G to T substitution at nucleotide position 499, causing the aspartic acid (D) at amino acid position 167 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.9	D;D;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.060	.;B;.
Vest4		0.48
MutPred		0.58		Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);.;
MVP		0.69
MPC		1.4
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.32
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-64603068;