Genetic Variant ROS1:p.Arg176Gln (chr6-117403216-C-T) – 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.527G>A(p.Arg176Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0793 in 1,611,816 control chromosomes in the GnomAD database, including 5,472 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.063 ( 372 hom., cov: 33)

Exomes 𝑓: 0.081 ( 5100 hom. )

Consequence

ROS1
NM_001378902.1 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.70

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:

ENSG00000282218 (HGNC:):

ENSG00000282218 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=0.0032022297).

BP6

Variant 6-117403216-C-T is Benign according to our data. Variant chr6-117403216-C-T is described in ClinVar as [Benign]. Clinvar id is 3387860.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROS1	NM_001378902.1 link	c.527G>A	p.Arg176Gln	missense_variant	Exon 7 of 44	ENST00000368507.8	NP_001365831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ROS1	ENST00000368507.8 link	c.527G>A	p.Arg176Gln	missense_variant	Exon 7 of 44	5	NM_001378902.1	ENSP00000357493.3	Q5H8Y1
ROS1	ENST00000368508.7 link	c.500G>A	p.Arg167Gln	missense_variant	Exon 6 of 43	1		ENSP00000357494.3	P08922
ENSG00000282218	ENST00000467125.1 link	c.548-81822G>A		intron_variant	Intron 4 of 6	2		ENSP00000487717.1	A0A0J9YVX5

Frequencies

GnomAD3 genomes

AF:

0.0629

AC:

9569

AN:

152114

Hom.:

372

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.168

Gnomad AMR

AF:

0.0664

Gnomad ASJ

AF:

0.0922

Gnomad EAS

AF:

0.0548

Gnomad SAS

AF:

0.0528

Gnomad FIN

AF:

0.0765

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0866

Gnomad OTH

AF:

0.0780

GnomAD3 exomes

AF:

0.0709

AC:

17662

AN:

248944

Hom.:

704

AF XY:

0.0727

AC XY:

9776

AN XY:

134456

show subpopulations

Gnomad AFR exome

AF:

0.0152

Gnomad AMR exome

AF:

0.0555

Gnomad ASJ exome

AF:

0.0976

Gnomad EAS exome

AF:

0.0611

Gnomad SAS exome

AF:

0.0560

Gnomad FIN exome

AF:

0.0758

Gnomad NFE exome

AF:

0.0853

Gnomad OTH exome

AF:

0.0804

GnomAD4 exome

AF:

0.0811

AC:

118328

AN:

1459584

Hom.:

5100

Cov.:

AF XY:

0.0804

AC XY:

58345

AN XY:

726000

show subpopulations

Gnomad4 AFR exome

AF:

0.0143

Gnomad4 AMR exome

AF:

0.0551

Gnomad4 ASJ exome

AF:

0.0939

Gnomad4 EAS exome

AF:

0.0569

Gnomad4 SAS exome

AF:

0.0567

Gnomad4 FIN exome

AF:

0.0781

Gnomad4 NFE exome

AF:

0.0868

Gnomad4 OTH exome

AF:

0.0794

GnomAD4 genome

AF:

0.0628

AC:

9562

AN:

152232

Hom.:

372

Cov.:

AF XY:

0.0622

AC XY:

4628

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0156

Gnomad4 AMR

AF:

0.0662

Gnomad4 ASJ

AF:

0.0922

Gnomad4 EAS

AF:

0.0548

Gnomad4 SAS

AF:

0.0526

Gnomad4 FIN

AF:

0.0765

Gnomad4 NFE

AF:

0.0866

Gnomad4 OTH

AF:

0.0767

Alfa

AF:

0.0826

Hom.:

1351

Bravo

AF:

0.0608

TwinsUK

AF:

0.0825

AC:

306

ALSPAC

AF:

0.0804

AC:

310

ESP6500AA

AF:

0.0179

AC:

ESP6500EA

AF:

0.0917

AC:

789

ExAC

AF:

0.0710

AC:

8625

Asia WGS

AF:

0.0460

AC:

160

AN:

3478

EpiCase

AF:

0.0909

EpiControl

AF:

0.0922

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 01, 2024

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

0.11

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

T;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.86

D;D

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.9

L;.

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.34

Sift

Benign

0.049

D;D

Sift4G

Benign

0.16

T;T

Polyphen

0.91

P;.

Vest4

0.47

MPC

0.18

ClinPred

0.023

GERP RS

4.4

Varity_R

0.37

gMVP

0.55

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

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