rs2273601

chr6-117409656-G-A

Variant summary

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

The NM_001378902.1(ROS1):c.256-14C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,609,760 control chromosomes in the GnomAD database, including 59,413 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (8420 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50993 hom.)
• Consequence: ROS1 NM_001378902.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.947

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 (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROS1	NM_001378902.1	c.256-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000368507.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROS1	ENST00000368507.8	c.256-14C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001378902.1	P1
ROS1	ENST00000368508.7	c.229-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47595 AN: 151920 Hom.: 8411 Cov.: 32

Gnomad AFR AF: 0.475

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.290

GnomAD3 exomes AF: 0.269 AC: 67489 AN: 250966 Hom.: 10372 AF XY: 0.275 AC XY: 37255 AN XY: 135608

Gnomad AFR exome AF: 0.479

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.272

Gnomad SAS exome AF: 0.420

Gnomad FIN exome AF: 0.306

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.255 AC: 371972 AN: 1457722 Hom.: 50993 Cov.: 31 AF XY: 0.260 AC XY: 188520 AN XY: 725418

Gnomad4 AFR exome AF: 0.491

Gnomad4 AMR exome AF: 0.137

Gnomad4 ASJ exome AF: 0.257

Gnomad4 EAS exome AF: 0.284

Gnomad4 SAS exome AF: 0.419

Gnomad4 FIN exome AF: 0.302

Gnomad4 NFE exome AF: 0.235

Gnomad4 OTH exome AF: 0.276

GnomAD4 genome AF: 0.313 AC: 47639 AN: 152038 Hom.: 8420 Cov.: 32 AF XY: 0.317 AC XY: 23538 AN XY: 74310

Gnomad4 AFR AF: 0.475

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.256

Gnomad4 EAS AF: 0.278

Gnomad4 SAS AF: 0.428

Gnomad4 FIN AF: 0.313

Gnomad4 NFE AF: 0.241

Gnomad4 OTH AF: 0.291

Alfa AF: 0.249 Hom.: 8603

Bravo AF: 0.307

Asia WGS AF: 0.365 AC: 1270 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	3.4
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -14

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

Publications

LitVar

Other links and lift over

dbSNP: rs2273601; hg19: chr6-117730819; COSMIC: COSV63852678;