NM_001378902.1:c.6773T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001378902.1(ROS1):​c.6773T>A​(p.Met2258Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2258T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ROS1
NM_001378902.1 missense

Scores

3
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.05

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27187485).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ROS1NM_001378902.1 linkc.6773T>A p.Met2258Lys missense_variant Exon 44 of 44 ENST00000368507.8 NP_001365831.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ROS1ENST00000368507.8 linkc.6773T>A p.Met2258Lys missense_variant Exon 44 of 44 5 NM_001378902.1 ENSP00000357493.3 Q5H8Y1
ROS1ENST00000368508.7 linkc.6791T>A p.Met2264Lys missense_variant Exon 43 of 43 1 ENSP00000357494.3 P08922

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461558
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727056
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33458
American (AMR)
AF:
0.00
AC:
0
AN:
44668
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26118
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86152
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53394
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111926
Other (OTH)
AF:
0.00
AC:
0
AN:
60378
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.048
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
14
DANN
Benign
0.91
DEOGEN2
Benign
0.075
T;.
Eigen
Benign
-0.80
Eigen_PC
Benign
-0.65
FATHMM_MKL
Benign
0.69
D
LIST_S2
Benign
0.62
T;T
M_CAP
Benign
0.025
D
MetaRNN
Benign
0.27
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.2
M;.
PhyloP100
1.0
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.50
N;N
REVEL
Benign
0.11
Sift
Uncertain
0.017
D;D
Sift4G
Uncertain
0.0070
D;D
Polyphen
0.0040
B;.
Vest4
0.51
MutPred
0.56
Gain of solvent accessibility (P = 0.007);.;
MVP
0.18
MPC
0.039
ClinPred
0.44
T
GERP RS
2.0
Varity_R
0.39
gMVP
0.40
Mutation Taster
=74/26
polymorphism

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

Other links and lift over

dbSNP: rs764807682; hg19: chr6-117609908; API