chr6-117301093-C-T

Variant names:

• chr6-117301093-C-T
• rs145104466
• NM_001378902.1:c.6596G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001378902.1(ROS1):​c.6596G>A​(p.Arg2199Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R2199I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ROS1 NM_001378902.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.28
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROS1	NM_001378902.1	c.6596G>A	p.Arg2199Lys	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	c.6596G>A	p.Arg2199Lys	missense_variant	Exon 43 of 44	5	NM_001378902.1	ENSP00000357493.3
ROS1	ENST00000368508.7	c.6614G>A	p.Arg2205Lys	missense_variant	Exon 42 of 43	1		ENSP00000357494.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;.
PhyloP100		4.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.71
MutPred		0.86		Gain of methylation at R2205 (P = 0.0121);.;
MVP		0.76
MPC		0.21
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.91
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145104466; hg19: chr6-117622256; COSMIC: COSV106525734; COSMIC: COSV106525734;