6-117301070-C-T

Variant summary

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

The NM_001378902.1(ROS1):c.6619G>A(p.Asp2207Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,602,860 control chromosomes in the GnomAD database, including 47,546 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 𝑓 0.19 (3241 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44305 hom.)
• 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026458502).
• 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	UniProt
ROS1	NM_001378902.1	c.6619G>A	p.Asp2207Asn	missense_variant	43/44	ENST00000368507.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROS1	ENST00000368507.8	c.6619G>A	p.Asp2207Asn	missense_variant	43/44	5	NM_001378902.1	P1
ROS1	ENST00000368508.7	c.6637G>A	p.Asp2213Asn	missense_variant	42/43	1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28437 AN: 151986 Hom.: 3244 Cov.: 32

Gnomad AFR AF: 0.0575

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.180

GnomAD3 exomes AF: 0.203 AC: 49500 AN: 243942 Hom.: 5539 AF XY: 0.205 AC XY: 27110 AN XY: 131964

Gnomad AFR exome AF: 0.0548

Gnomad AMR exome AF: 0.151

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.177

Gnomad SAS exome AF: 0.145

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.213

GnomAD4 exome AF: 0.241 AC: 349551 AN: 1450756 Hom.: 44305 Cov.: 31 AF XY: 0.239 AC XY: 172022 AN XY: 721242

Gnomad4 AFR exome AF: 0.0508

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.204

Gnomad4 EAS exome AF: 0.165

Gnomad4 SAS exome AF: 0.149

Gnomad4 FIN exome AF: 0.237

Gnomad4 NFE exome AF: 0.262

Gnomad4 OTH exome AF: 0.225

GnomAD4 genome AF: 0.187 AC: 28437 AN: 152104 Hom.: 3241 Cov.: 32 AF XY: 0.184 AC XY: 13670 AN XY: 74346

Gnomad4 AFR AF: 0.0575

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.219

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.265

Gnomad4 OTH AF: 0.178

Alfa AF: 0.239 Hom.: 11728

Bravo AF: 0.176

TwinsUK AF: 0.249 AC: 925

ALSPAC AF: 0.257 AC: 989

ESP6500AA AF: 0.0688 AC: 303

ESP6500EA AF: 0.259 AC: 2231

ExAC AF: 0.208 AC: 25274

Asia WGS AF: 0.154 AC: 537 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.89	L;.
MutationTaster	Benign	0.98	P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.16
Sift	Benign	0.18	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.0090	B;.
Vest4		0.14
MPC		0.031
ClinPred		0.013	T
GERP RS		3.2
Varity_R		0.25
gMVP		0.32

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; COSMIC: COSV63850799; COSMIC: COSV63850799;