chr6-117301021-G-C

Variant names:

• chr6-117301021-G-C
• rs619203
• NM_001378902.1:c.6668C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3215 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43948 hom.)
• Consequence: ROS1 NM_001378902.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0410
• Publications: 44 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013863772).
• BP6: Variant 6-117301021-G-C is Benign according to our data. Variant chr6-117301021-G-C is described in ClinVar as [Benign]. Clinvar id is 3770428.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 rank	MANE	Protein	UniProt
ROS1	NM_001378902.1	c.6668C>G	p.Ser2223Cys	missense_variant	Exon 43 of 44	ENST00000368507.8	NP_001365831.1

Ensembl

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

GnomAD2 exomes AF: 0.199 AC: 47656 AN: 239274 AF XY: 0.202

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 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

African (AFR) AF: 0.0567 AC: 1875 AN: 33058

American (AMR) AF: 0.149 AC: 6240 AN: 41866

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 5226 AN: 25850

East Asian (EAS) AF: 0.164 AC: 6389 AN: 39018

South Asian (SAS) AF: 0.145 AC: 11902 AN: 82028

European-Finnish (FIN) AF: 0.236 AC: 12567 AN: 53152

Middle Eastern (MID) AF: 0.178 AC: 1022 AN: 5730

European-Non Finnish (NFE) AF: 0.261 AC: 287698 AN: 1102076

Other (OTH) AF: 0.224 AC: 13377 AN: 59662

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

African (AFR) AF: 0.0632 AC: 2623 AN: 41480

American (AMR) AF: 0.164 AC: 2509 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 755 AN: 3464

East Asian (EAS) AF: 0.172 AC: 886 AN: 5152

South Asian (SAS) AF: 0.161 AC: 774 AN: 4816

European-Finnish (FIN) AF: 0.231 AC: 2431 AN: 10516

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.265 AC: 18010 AN: 67940

Other (OTH) AF: 0.179 AC: 379 AN: 2112

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ROS1: BP4, BS1, BS2 -

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;.
PhyloP100		-0.041
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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs619203; hg19: chr6-117622184; COSMIC: COSV63850786; COSMIC: COSV63850786;