6-117403216-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002944.3(ROS1):c.500G>A(p.Arg167Gln) 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_002944.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.70

Publications

36 publications found

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 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

ROS1 links:

ENSG00000282218 (HGNC:):

ENSG00000282218 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ROS1	NM_001378902.1	MANE Select	c.527G>A	p.Arg176Gln	missense	Exon 7 of 44	NP_001365831.1
ROS1	NM_002944.3		c.500G>A	p.Arg167Gln	missense	Exon 6 of 43	NP_002935.2
ROS1	NM_001378891.1		c.527G>A	p.Arg176Gln	missense	Exon 7 of 44	NP_001365820.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ROS1	ENST00000368507.8	TSL:5 MANE Select	c.527G>A	p.Arg176Gln	missense	Exon 7 of 44	ENSP00000357493.3
ROS1	ENST00000368508.7	TSL:1	c.500G>A	p.Arg167Gln	missense	Exon 6 of 43	ENSP00000357494.3
ENSG00000282218	ENST00000467125.1	TSL:2	c.548-81822G>A		intron	N/A	ENSP00000487717.1

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

GnomAD2 exomes

AF:

0.0709

AC:

17662

AN:

248944

AF XY:

0.0727

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 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

African (AFR)

AF:

0.0143

AC:

476

AN:

33256

American (AMR)

AF:

0.0551

AC:

2428

AN:

44074

Ashkenazi Jewish (ASJ)

AF:

0.0939

AC:

2447

AN:

26052

East Asian (EAS)

AF:

0.0569

AC:

2258

AN:

39678

South Asian (SAS)

AF:

0.0567

AC:

4852

AN:

85648

European-Finnish (FIN)

AF:

0.0781

AC:

4173

AN:

53410

Middle Eastern (MID)

AF:

0.0830

AC:

476

AN:

5736

European-Non Finnish (NFE)

AF:

0.0868

AC:

96429

AN:

1111416

Other (OTH)

AF:

0.0794

AC:

4789

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

5282

10564

15846

21128

26410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3550

7100

10650

14200

17750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0628

AC:

9562

AN:

152232

Hom.:

372

Cov.:

AF XY:

0.0622

AC XY:

4628

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0156

AC:

648

AN:

41562

American (AMR)

AF:

0.0662

AC:

1012

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0922

AC:

320

AN:

3470

East Asian (EAS)

AF:

0.0548

AC:

283

AN:

5168

South Asian (SAS)

AF:

0.0526

AC:

254

AN:

4828

European-Finnish (FIN)

AF:

0.0765

AC:

810

AN:

10588

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0866

AC:

5892

AN:

68014

Other (OTH)

AF:

0.0767

AC:

162

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

457

913

1370

1826

2283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0788

Hom.:

2340

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0032

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.9

PhyloP100

2.7

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.34

Sift

Benign

0.049

Sift4G

Benign

0.16

Polyphen

0.91

Vest4

0.47

MPC

0.18

ClinPred

0.023

GERP RS

4.4

Varity_R

0.37

gMVP

0.55

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over