chr6-117301013-C-T

Variant names:

• chr6-117301013-C-T
• rs1275344272
• NM_001378902.1:c.6676G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001378902.1(ROS1):​c.6676G>A​(p.Glu2226Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ROS1 NM_001378902.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.946
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054592878).

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.6676G>A	p.Glu2226Lys	missense	Exon 43 of 44	NP_001365831.1	Q5H8Y1
	ROS1	NM_002944.3		c.6694G>A	p.Glu2232Lys	missense	Exon 42 of 43	NP_002935.2
	ROS1	NM_001378891.1		c.6682G>A	p.Glu2228Lys	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.6676G>A	p.Glu2226Lys	missense	Exon 43 of 44	ENSP00000357493.3	Q5H8Y1
	ROS1	ENST00000368508.7	TSL:1	c.6694G>A	p.Glu2232Lys	missense	Exon 42 of 43	ENSP00000357494.3	P08922
	ROS1	ENST00000957000.1		c.6721G>A	p.Glu2241Lys	missense	Exon 43 of 44	ENSP00000627059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438084 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 714230

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32570

American (AMR) AF: 0.00 AC: 0 AN: 39722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25602

East Asian (EAS) AF: 0.00 AC: 0 AN: 38780

South Asian (SAS) AF: 0.00 AC: 0 AN: 80000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1103028

Other (OTH) AF: 0.00 AC: 0 AN: 59462

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.95
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.054
Sift	Benign	0.42	T
Sift4G	Benign	0.64	T
Polyphen		0.0010	B
Vest4		0.27
MutPred		0.35		Gain of ubiquitination at E2232 (P = 0.006)
MVP		0.20
MPC		0.027
ClinPred		0.096	T
GERP RS		2.1
Varity_R		0.030
gMVP		0.38
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs1275344272; hg19: chr6-117622176;