Genetic Variant ROS1:p.Glu1896Lys (chr6-117321332-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001378902.1(ROS1):c.5686G>A(p.Glu1896Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,613,670 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0088 ( 18 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 72 hom. )

Consequence

ROS1
NM_001378902.1 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.37

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=0.003884554).

BP6

Variant 6-117321332-C-T is Benign according to our data. Variant chr6-117321332-C-T is described in ClinVar as [Benign]. Clinvar id is 770558.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00882 (1342/152218) while in subpopulation EAS AF= 0.0399 (206/5166). AF 95% confidence interval is 0.0354. There are 18 homozygotes in gnomad4. There are 705 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROS1	NM_001378902.1 link	c.5686G>A	p.Glu1896Lys	missense_variant	Exon 36 of 44	ENST00000368507.8	NP_001365831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ROS1	ENST00000368507.8 link	c.5686G>A	p.Glu1896Lys	missense_variant	Exon 36 of 44	5	NM_001378902.1	ENSP00000357493.3	Q5H8Y1
ROS1	ENST00000368508.7 link	c.5704G>A	p.Glu1902Lys	missense_variant	Exon 35 of 43	1		ENSP00000357494.3	P08922
ENSG00000282218	ENST00000467125.1 link	c.610G>A	p.Glu204Lys	missense_variant	Exon 5 of 7	2		ENSP00000487717.1	A0A0J9YVX5

Frequencies

GnomAD3 genomes

AF:

0.00882

AC:

1341

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00728

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.0400

Gnomad SAS

AF:

0.0240

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00801

AC:

2010

AN:

250980

Hom.:

AF XY:

0.00810

AC XY:

1099

AN XY:

135672

show subpopulations

Gnomad AFR exome

AF:

0.0195

Gnomad AMR exome

AF:

0.00322

Gnomad ASJ exome

AF:

0.00547

Gnomad EAS exome

AF:

0.0404

Gnomad SAS exome

AF:

0.0206

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.00620

GnomAD4 exome

AF:

0.00353

AC:

5155

AN:

1461452

Hom.:

Cov.:

AF XY:

0.00393

AC XY:

2854

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.0209

Gnomad4 AMR exome

AF:

0.00406

Gnomad4 ASJ exome

AF:

0.00574

Gnomad4 EAS exome

AF:

0.0331

Gnomad4 SAS exome

AF:

0.0184

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000633

Gnomad4 OTH exome

AF:

0.00798

GnomAD4 genome

AF:

0.00882

AC:

1342

AN:

152218

Hom.:

Cov.:

AF XY:

0.00947

AC XY:

705

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0193

Gnomad4 AMR

AF:

0.00727

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.0399

Gnomad4 SAS

AF:

0.0241

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000882

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00369

Hom.:

Bravo

AF:

0.00942

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.0182

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00832

AC:

1010

Asia WGS

AF:

0.0390

AC:

135

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00166

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;.

Eigen

Benign

-0.015

Eigen_PC

Benign

0.029

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

D;D;D

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.6

M;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.1

N;N;.

REVEL

Benign

0.073

Sift

Benign

0.25

T;T;.

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.92

P;.;.

Vest4

0.35

MVP

0.45

MPC

0.085

ClinPred

0.029

GERP RS

4.3

Varity_R

0.074

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