Genetic Variant ROS1:c.5348+9G>A (chr6-117329320-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001378902.1(ROS1):c.5348+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,256,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

ROS1
NM_001378902.1 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0540

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 6-117329320-C-T is Benign according to our data. Variant chr6-117329320-C-T is described in ClinVar as Benign. ClinVar VariationId is 784096.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ROS1	NM_001378902.1	MANE Select	c.5348+9G>A	intron	N/A	NP_001365831.1	Q5H8Y1
ROS1	NM_002944.3		c.5366+9G>A	intron	N/A	NP_002935.2
ROS1	NM_001378891.1		c.5354+9G>A	intron	N/A	NP_001365820.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ROS1	ENST00000368507.8	TSL:5 MANE Select	c.5348+9G>A	intron	N/A	ENSP00000357493.3	Q5H8Y1
ROS1	ENST00000368508.7	TSL:1	c.5366+9G>A	intron	N/A	ENSP00000357494.3	P08922
ENSG00000282218	ENST00000467125.1	TSL:2	c.548-7926G>A	intron	N/A	ENSP00000487717.1	A0A0J9YVX5

Frequencies

GnomAD3 genomes

AF:

0.000815

AC:

124

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000241

AC:

AN:

232800

AF XY:

0.000199

show subpopulations

Gnomad AFR exome

AF:

0.00329

Gnomad AMR exome

AF:

0.000102

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000921

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000861

AC:

AN:

1103928

Hom.:

Cov.:

AF XY:

0.0000690

AC XY:

AN XY:

564854

show subpopulations

African (AFR)

AF:

0.00324

AC:

AN:

25584

American (AMR)

AF:

0.0000515

AC:

AN:

38814

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23056

East Asian (EAS)

AF:

0.00

AC:

AN:

37752

South Asian (SAS)

AF:

0.0000136

AC:

AN:

73460

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5046

European-Non Finnish (NFE)

AF:

0.00000501

AC:

AN:

799070

Other (OTH)

AF:

0.000103

AC:

AN:

48540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000814

AC:

124

AN:

152318

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00284

AC:

118

AN:

41574

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000561

Hom.:

Bravo

AF:

0.000892

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

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

BayesDel_noAF

Benign

-0.82

CADD

Benign

9.8

(source)

DANN

Benign

0.41

PhyloP100

0.054

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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