6-117329351-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001378902.1(ROS1):​c.5326A>C​(p.Thr1776Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000581 in 1,531,544 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000059 ( 1 hom. )

Consequence

ROS1
NM_001378902.1 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.566
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1491242).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ROS1NM_001378902.1 linkc.5326A>C p.Thr1776Pro missense_variant Exon 33 of 44 ENST00000368507.8 NP_001365831.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ROS1ENST00000368507.8 linkc.5326A>C p.Thr1776Pro missense_variant Exon 33 of 44 5 NM_001378902.1 ENSP00000357493.3 Q5H8Y1
ROS1ENST00000368508.7 linkc.5344A>C p.Thr1782Pro missense_variant Exon 32 of 43 1 ENSP00000357494.3 P08922
ENSG00000282218ENST00000467125.1 linkc.548-7957A>C intron_variant Intron 4 of 6 2 ENSP00000487717.1 A0A0J9YVX5
ROS1ENST00000403284.2 linkc.265A>C p.Thr89Pro missense_variant Exon 2 of 3 2 ENSP00000384647.2 H0Y3T9

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152230
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000561
AC:
14
AN:
249428
Hom.:
0
AF XY:
0.0000445
AC XY:
6
AN XY:
134776
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.0000999
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000115
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000587
AC:
81
AN:
1379314
Hom.:
1
Cov.:
23
AF XY:
0.0000506
AC XY:
35
AN XY:
691048
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000390
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000742
Gnomad4 OTH exome
AF:
0.0000521
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152230
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00000601
Hom.:
0
Bravo
AF:
0.0000567
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 07, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.5344A>C (p.T1782P) alteration is located in exon 32 (coding exon 32) of the ROS1 gene. This alteration results from a A to C substitution at nucleotide position 5344, causing the threonine (T) at amino acid position 1782 to be replaced by a proline (P). 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
0.14
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
15
DANN
Benign
0.88
DEOGEN2
Uncertain
0.52
D;.;.
Eigen
Benign
-0.77
Eigen_PC
Benign
-0.83
FATHMM_MKL
Benign
0.082
N
LIST_S2
Benign
0.30
T;T;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Uncertain
2.8
M;.;.
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-2.1
N;N;D
REVEL
Benign
0.18
Sift
Benign
0.21
T;T;T
Sift4G
Uncertain
0.054
T;T;D
Polyphen
0.052
B;.;.
Vest4
0.23
MVP
0.13
MPC
0.039
ClinPred
0.061
T
GERP RS
-1.9
Varity_R
0.37
gMVP
0.62

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.20
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.20
Position offset: -22

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.

Other links and lift over

dbSNP: rs149390376; hg19: chr6-117650514; API