rs545537

Variant names:

• chr6-117323878-C-T
• rs545537
• NM_001378902.1:c.5623+454G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001378902.1(ROS1):​c.5623+454G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 152,132 control chromosomes in the GnomAD database, including 1,096 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1096 hom., cov: 32)
• Consequence: ROS1 NM_001378902.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.582
• Publications: 3 publications found

Genes affected

ROS1 (HGNC:10261): (ROS proto-oncogene 1, receptor tyrosine kinase) This proto-oncogene, highly-expressed in a variety of tumor cell lines, belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes. The protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity. The protein may function as a growth or differentiation factor receptor. [provided by RefSeq, Jul 2008]

ROS1 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000282218 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378902.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROS1	NM_001378902.1	MANE Select	c.5623+454G>A		intron	N/A	NP_001365831.1
	ROS1	NM_002944.3		c.5641+454G>A		intron	N/A	NP_002935.2
	ROS1	NM_001378891.1		c.5629+454G>A		intron	N/A	NP_001365820.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROS1	ENST00000368507.8	TSL:5 MANE Select	c.5623+454G>A		intron	N/A	ENSP00000357493.3
	ROS1	ENST00000368508.7	TSL:1	c.5641+454G>A		intron	N/A	ENSP00000357494.3
	ENSG00000282218	ENST00000467125.1	TSL:2	c.548-2484G>A		intron	N/A	ENSP00000487717.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17447 AN: 152014 Hom.: 1096 Cov.: 32

Gnomad AFR AF: 0.0728

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.123

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.115 AC: 17460 AN: 152132 Hom.: 1096 Cov.: 32 AF XY: 0.115 AC XY: 8519 AN XY: 74352

African (AFR) AF: 0.0727 AC: 3020 AN: 41544

American (AMR) AF: 0.120 AC: 1832 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 618 AN: 3472

East Asian (EAS) AF: 0.179 AC: 922 AN: 5160

South Asian (SAS) AF: 0.136 AC: 656 AN: 4814

European-Finnish (FIN) AF: 0.112 AC: 1180 AN: 10578

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8702 AN: 67986

Other (OTH) AF: 0.125 AC: 265 AN: 2112

Alfa AF: 0.125 Hom.: 747

Bravo AF: 0.116

Asia WGS AF: 0.149 AC: 520 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.0
DANN	Benign	0.73
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

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: rs545537; hg19: chr6-117645041; COSMIC: COSV63853941;