6-117301070-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378902.1(ROS1):c.6619G>C(p.Asp2207His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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. D2207E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ROS1 NM_001378902.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.924

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]

ACMG classification

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=0.20343053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROS1	NM_001378902.1	c.6619G>C	p.Asp2207His	missense_variant	43/44	ENST00000368507.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROS1	ENST00000368507.8	c.6619G>C	p.Asp2207His	missense_variant	43/44	5	NM_001378902.1	P1
ROS1	ENST00000368508.7	c.6637G>C	p.Asp2213His	missense_variant	42/43	1

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	Benign	0.13
BayesDel_addAF	Benign	-0.0084	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	19
Dann	Benign	0.92
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.90	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.14
Sift	Benign	0.19	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.080	B;.
Vest4		0.41
MutPred		0.34		Gain of MoRF binding (P = 0.0822);.;
MVP		0.41
MPC		0.039
ClinPred		0.39	T
GERP RS		3.2
Varity_R		0.30
gMVP		0.49

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

LitVar

Other links and lift over

dbSNP: rs529038; hg19: chr6-117622233;