6-117301021-G-C

Position:

• chr6-117301021-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378902.1(ROS1):​c.6668C>G​(p.Ser2223Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,594,404 control chromosomes in the GnomAD database, including 47,163 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (3215 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43948 hom.)
• Consequence: ROS1 NM_001378902.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0410

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013863772).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROS1	NM_001378902.1	c.6668C>G	p.Ser2223Cys	missense_variant	43/44	ENST00000368507.8	NP_001365831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROS1	ENST00000368507.8	c.6668C>G	p.Ser2223Cys	missense_variant	43/44	5	NM_001378902.1	ENSP00000357493.3
ROS1	ENST00000368508.7	c.6686C>G	p.Ser2229Cys	missense_variant	42/43	1		ENSP00000357494.3

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28628 AN: 151846 Hom.: 3217 Cov.: 32

Gnomad AFR AF: 0.0632

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.181

GnomAD3 exomes AF: 0.199 AC: 47656 AN: 239274 Hom.: 5179 AF XY: 0.202 AC XY: 26166 AN XY: 129520

Gnomad AFR exome AF: 0.0586

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.172

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.240 AC: 346296 AN: 1442440 Hom.: 43948 Cov.: 30 AF XY: 0.238 AC XY: 170291 AN XY: 716898

Gnomad4 AFR exome AF: 0.0567

Gnomad4 AMR exome AF: 0.149

Gnomad4 ASJ exome AF: 0.202

Gnomad4 EAS exome AF: 0.164

Gnomad4 SAS exome AF: 0.145

Gnomad4 FIN exome AF: 0.236

Gnomad4 NFE exome AF: 0.261

Gnomad4 OTH exome AF: 0.224

GnomAD4 genome AF: 0.188 AC: 28632 AN: 151964 Hom.: 3215 Cov.: 32 AF XY: 0.185 AC XY: 13740 AN XY: 74242

Gnomad4 AFR AF: 0.0632

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.172

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.265

Gnomad4 OTH AF: 0.179

Alfa AF: 0.246 Hom.: 3675

Bravo AF: 0.178

TwinsUK AF: 0.246 AC: 911

ALSPAC AF: 0.250 AC: 963

ESP6500AA AF: 0.0742 AC: 327

ESP6500EA AF: 0.260 AC: 2234

ExAC AF: 0.208 AC: 25272

Asia WGS AF: 0.155 AC: 543 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.0
DANN	Benign	0.77
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.17	T;T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.3	N;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.0	N;N
REVEL	Benign	0.11
Sift	Benign	0.97	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.080
MPC		0.025
ClinPred		0.00014	T
GERP RS		2.2
Varity_R		0.12
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs619203; hg19: chr6-117622184; COSMIC: COSV63850786; COSMIC: COSV63850786;