NM_001378902.1:c.6664A>C

Variant names:

• chr6-117301025-T-G
• rs529156
• NM_001378902.1:c.6664A>C

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.6664A>C​(p.Lys2222Gln) 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 1,597,896 control chromosomes in the GnomAD database, including 47,339 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 (3218 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44121 hom.)
• Consequence: ROS1 NM_001378902.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.05
• Publications: 33 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=0.0027093291).
• BP6: Variant 6-117301025-T-G is Benign according to our data. Variant chr6-117301025-T-G is described in ClinVar as Benign. ClinVar VariationId is 3770429.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378902.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROS1	NM_001378902.1	MANE Select	c.6664A>C	p.Lys2222Gln	missense	Exon 43 of 44	NP_001365831.1	Q5H8Y1
	ROS1	NM_002944.3		c.6682A>C	p.Lys2228Gln	missense	Exon 42 of 43	NP_002935.2
	ROS1	NM_001378891.1		c.6670A>C	p.Lys2224Gln	missense	Exon 43 of 44	NP_001365820.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROS1	ENST00000368507.8	TSL:5 MANE Select	c.6664A>C	p.Lys2222Gln	missense	Exon 43 of 44	ENSP00000357493.3	Q5H8Y1
	ROS1	ENST00000368508.7	TSL:1	c.6682A>C	p.Lys2228Gln	missense	Exon 42 of 43	ENSP00000357494.3	P08922
	ROS1	ENST00000957000.1		c.6709A>C	p.Lys2237Gln	missense	Exon 43 of 44	ENSP00000627059.1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28636 AN: 151980 Hom.: 3220 Cov.: 32

Gnomad AFR AF: 0.0631

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: 0.201 AC: 48538 AN: 242014 AF XY: 0.203

Gnomad AFR exome AF: 0.0586

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.175

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.250

Gnomad OTH exome AF: 0.212

GnomAD4 exome AF: 0.240 AC: 347400 AN: 1445798 Hom.: 44121 Cov.: 31 AF XY: 0.238 AC XY: 170919 AN XY: 718810

African (AFR) AF: 0.0571 AC: 1896 AN: 33198

American (AMR) AF: 0.151 AC: 6445 AN: 42546

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 5269 AN: 25944

East Asian (EAS) AF: 0.164 AC: 6437 AN: 39174

South Asian (SAS) AF: 0.146 AC: 12116 AN: 82928

European-Finnish (FIN) AF: 0.237 AC: 12583 AN: 53180

Middle Eastern (MID) AF: 0.178 AC: 1023 AN: 5742

European-Non Finnish (NFE) AF: 0.261 AC: 288211 AN: 1103286

Other (OTH) AF: 0.224 AC: 13420 AN: 59800

GnomAD4 genome AF: 0.188 AC: 28640 AN: 152098 Hom.: 3218 Cov.: 32 AF XY: 0.185 AC XY: 13744 AN XY: 74316

African (AFR) AF: 0.0631 AC: 2624 AN: 41560

American (AMR) AF: 0.164 AC: 2510 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 755 AN: 3466

East Asian (EAS) AF: 0.172 AC: 884 AN: 5146

South Asian (SAS) AF: 0.161 AC: 774 AN: 4820

European-Finnish (FIN) AF: 0.231 AC: 2433 AN: 10552

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

European-Non Finnish (NFE) AF: 0.265 AC: 18016 AN: 67952

Other (OTH) AF: 0.179 AC: 379 AN: 2114

Alfa AF: 0.231 Hom.: 13137

Bravo AF: 0.178

TwinsUK AF: 0.246 AC: 911

ALSPAC AF: 0.250 AC: 964

ESP6500AA AF: 0.0742 AC: 327

ESP6500EA AF: 0.260 AC: 2234

ExAC AF: 0.208 AC: 25266

Asia WGS AF: 0.155 AC: 542 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.3	N
PhyloP100		1.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.065
Sift	Benign	0.65	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.056
MPC		0.026
ClinPred		0.0014	T
GERP RS		4.1
Varity_R		0.20
gMVP		0.19
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs529156; hg19: chr6-117622188; COSMIC: COSV63850793; COSMIC: COSV63850793;