chr6-117409656-G-A

Variant names:

• chr6-117409656-G-A
• rs2273601
• NM_001378902.1:c.256-14C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378902.1(ROS1):​c.256-14C>T variant causes a 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 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.947
• Publications: 18 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

ENSG00000282218 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ROS1	NM_001378902.1	c.256-14C>T		intron_variant	Intron 4 of 43	ENST00000368507.8	NP_001365831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROS1	ENST00000368507.8	c.256-14C>T		intron_variant	Intron 4 of 43	5	NM_001378902.1	ENSP00000357493.3
ROS1	ENST00000368508.7	c.229-14C>T		intron_variant	Intron 3 of 42	1		ENSP00000357494.3
ENSG00000282218	ENST00000467125.1	c.548-88262C>T		intron_variant	Intron 4 of 6	2		ENSP00000487717.1

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

GnomAD2 exomes AF: 0.269 AC: 67489 AN: 250966 AF XY: 0.275

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 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

African (AFR) AF: 0.491 AC: 16378 AN: 33342

American (AMR) AF: 0.137 AC: 6105 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 6699 AN: 26098

East Asian (EAS) AF: 0.284 AC: 11247 AN: 39666

South Asian (SAS) AF: 0.419 AC: 36059 AN: 86154

European-Finnish (FIN) AF: 0.302 AC: 16120 AN: 53374

Middle Eastern (MID) AF: 0.353 AC: 2030 AN: 5758

European-Non Finnish (NFE) AF: 0.235 AC: 260718 AN: 1108436

Other (OTH) AF: 0.276 AC: 16616 AN: 60252

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

African (AFR) AF: 0.475 AC: 19688 AN: 41462

American (AMR) AF: 0.192 AC: 2935 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 887 AN: 3464

East Asian (EAS) AF: 0.278 AC: 1438 AN: 5172

South Asian (SAS) AF: 0.428 AC: 2058 AN: 4810

European-Finnish (FIN) AF: 0.313 AC: 3305 AN: 10554

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.241 AC: 16361 AN: 67976

Other (OTH) AF: 0.291 AC: 615 AN: 2110

Alfa AF: 0.259 Hom.: 21629

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
PhyloP100		0.95
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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