Genetic Variant ROS1:p.Lys2222Gln (chr6-117301025-T-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001378902.1(ROS1):c.6664A>C(p.Lys2222Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,597,896 control chromosomes in the GnomAD database, including 47,339 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.19 ( 3218 hom., cov: 32)

Exomes 𝑓: 0.24 ( 44121 hom. )

Consequence

ROS1
NM_001378902.1 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.05

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027093291).

BP6

Variant 6-117301025-T-G is Benign according to our data. Variant chr6-117301025-T-G is described in ClinVar as [Benign]. Clinvar id is 3770429.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROS1	NM_001378902.1 link	c.6664A>C	p.Lys2222Gln	missense_variant	Exon 43 of 44	ENST00000368507.8	NP_001365831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROS1	ENST00000368507.8 link	c.6664A>C	p.Lys2222Gln	missense_variant	Exon 43 of 44	5	NM_001378902.1	ENSP00000357493.3		Q5H8Y1
ROS1	ENST00000368508.7 link	c.6682A>C	p.Lys2228Gln	missense_variant	Exon 42 of 43	1		ENSP00000357494.3		P08922

Frequencies

GnomAD3 genomes

AF:

0.188

AC:

28636

AN:

151980

Hom.:

3220

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0631

Gnomad AMI

AF:

0.239

Gnomad AMR

AF:

0.164

Gnomad ASJ

AF:

0.218

Gnomad EAS

AF:

0.172

Gnomad SAS

AF:

0.160

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.153

Gnomad NFE

AF:

0.265

Gnomad OTH

AF:

0.181

GnomAD3 exomes

AF:

0.201

AC:

48538

AN:

242014

Hom.:

5329

AF XY:

0.203

AC XY:

26625

AN XY:

130968

show subpopulations

Gnomad AFR exome

AF:

0.0586

Gnomad AMR exome

AF:

0.145

Gnomad ASJ exome

AF:

0.197

Gnomad EAS exome

AF:

0.175

Gnomad SAS exome

AF:

0.141

Gnomad FIN exome

AF:

0.231

Gnomad NFE exome

AF:

0.250

Gnomad OTH exome

AF:

0.212

GnomAD4 exome

AF:

0.240

AC:

347400

AN:

1445798

Hom.:

44121

Cov.:

AF XY:

0.238

AC XY:

170919

AN XY:

718810

show subpopulations

Gnomad4 AFR exome

AF:

0.0571

Gnomad4 AMR exome

AF:

0.151

Gnomad4 ASJ exome

AF:

0.203

Gnomad4 EAS exome

AF:

0.164

Gnomad4 SAS exome

AF:

0.146

Gnomad4 FIN exome

AF:

0.237

Gnomad4 NFE exome

AF:

0.261

Gnomad4 OTH exome

AF:

0.224

GnomAD4 genome

AF:

0.188

AC:

28640

AN:

152098

Hom.:

3218

Cov.:

AF XY:

0.185

AC XY:

13744

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0631

Gnomad4 AMR

AF:

0.164

Gnomad4 ASJ

AF:

0.218

Gnomad4 EAS

AF:

0.172

Gnomad4 SAS

AF:

0.161

Gnomad4 FIN

AF:

0.231

Gnomad4 NFE

AF:

0.265

Gnomad4 OTH

AF:

0.179

Alfa

AF:

0.241

Hom.:

10819

Bravo

AF:

0.178

TwinsUK

AF:

0.246

AC:

911

ALSPAC

AF:

0.250

AC:

964

ESP6500AA

AF:

0.0742

AC:

327

ESP6500EA

AF:

0.260

AC:

2234

ExAC

AF:

0.208

AC:

25266

Asia WGS

AF:

0.155

AC:

542

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ROS1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.069

T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.27

T;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-2.3

N;.

PrimateAI

Benign

0.27

PROVEAN

Benign

0.50

N;N

REVEL

Benign

0.065

Sift

Benign

0.65

T;T

Sift4G

Benign

0.62

T;T

Polyphen

0.0

B;.

Vest4

0.056

MPC

0.026

ClinPred

0.0014

GERP RS

4.1

Varity_R

0.20

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over