Genetic Variant ROS1:p.Asn2229Ser (chr6-117301003-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001378902.1(ROS1):c.6686A>G(p.Asn2229Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,436,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

ROS1
NM_001378902.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.780

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035444736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROS1	NM_001378902.1 link	c.6686A>G	p.Asn2229Ser	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.6686A>G	p.Asn2229Ser	missense_variant	Exon 43 of 44	5	NM_001378902.1	ENSP00000357493.3		Q5H8Y1
ROS1	ENST00000368508.7 link	c.6704A>G	p.Asn2235Ser	missense_variant	Exon 42 of 43	1		ENSP00000357494.3		P08922

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000349

AC:

AN:

229550

AF XY:

0.0000322

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000746

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000125

AC:

AN:

1436696

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

713424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32478

American (AMR)

AF:

0.00

AC:

AN:

39150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25582

East Asian (EAS)

AF:

0.00

AC:

AN:

38778

South Asian (SAS)

AF:

0.00

AC:

AN:

79732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53216

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.0000127

AC:

AN:

1102626

Other (OTH)

AF:

0.0000337

AC:

AN:

59428

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.6704A>G (p.N2235S) alteration is located in exon 42 (coding exon 42) of the ROS1 gene. This alteration results from a A to G substitution at nucleotide position 6704, causing the asparagine (N) at amino acid position 2235 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.8

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.073

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.15

T;T

M_CAP

Benign

0.0092

MetaRNN

Benign

0.035

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.69

N;.

PhyloP100

0.78

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.39

N;N

REVEL

Benign

0.067

Sift

Benign

0.95

T;T

Sift4G

Benign

0.65

T;T

Polyphen

0.0

B;.

Vest4

0.055

MutPred

0.23

Gain of phosphorylation at N2235 (P = 0.044);.;

MVP

0.23

MPC

0.023

ClinPred

0.062

GERP RS

0.95

Varity_R

0.021

gMVP

0.11

Mutation Taster

=90/10

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr6-117301003-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over