6-117403216-C-T

Variant summary

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

The NM_001378902.1(ROS1):c.527G>A(p.Arg176Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0793 in 1,611,816 control chromosomes in the GnomAD database, including 5,472 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 0.063 (372 hom., cov: 33)
  • Exomes 𝑓: 0.081 (5100 hom.)
• Consequence: ROS1 NM_001378902.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.70

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 (MetaRNN=0.0032022297).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROS1	NM_001378902.1	c.527G>A	p.Arg176Gln	missense_variant	7/44	ENST00000368507.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROS1	ENST00000368507.8	c.527G>A	p.Arg176Gln	missense_variant	7/44	5	NM_001378902.1	P1
ROS1	ENST00000368508.7	c.500G>A	p.Arg167Gln	missense_variant	6/43	1

Frequencies

GnomAD3 genomes AF: 0.0629 AC: 9569 AN: 152114 Hom.: 372 Cov.: 33

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.0664

Gnomad ASJ AF: 0.0922

Gnomad EAS AF: 0.0548

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.0765

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0866

Gnomad OTH AF: 0.0780

GnomAD3 exomes AF: 0.0709 AC: 17662 AN: 248944 Hom.: 704 AF XY: 0.0727 AC XY: 9776 AN XY: 134456

Gnomad AFR exome AF: 0.0152

Gnomad AMR exome AF: 0.0555

Gnomad ASJ exome AF: 0.0976

Gnomad EAS exome AF: 0.0611

Gnomad SAS exome AF: 0.0560

Gnomad FIN exome AF: 0.0758

Gnomad NFE exome AF: 0.0853

Gnomad OTH exome AF: 0.0804

GnomAD4 exome AF: 0.0811 AC: 118328 AN: 1459584 Hom.: 5100 Cov.: 32 AF XY: 0.0804 AC XY: 58345 AN XY: 726000

Gnomad4 AFR exome AF: 0.0143

Gnomad4 AMR exome AF: 0.0551

Gnomad4 ASJ exome AF: 0.0939

Gnomad4 EAS exome AF: 0.0569

Gnomad4 SAS exome AF: 0.0567

Gnomad4 FIN exome AF: 0.0781

Gnomad4 NFE exome AF: 0.0868

Gnomad4 OTH exome AF: 0.0794

GnomAD4 genome AF: 0.0628 AC: 9562 AN: 152232 Hom.: 372 Cov.: 33 AF XY: 0.0622 AC XY: 4628 AN XY: 74428

Gnomad4 AFR AF: 0.0156

Gnomad4 AMR AF: 0.0662

Gnomad4 ASJ AF: 0.0922

Gnomad4 EAS AF: 0.0548

Gnomad4 SAS AF: 0.0526

Gnomad4 FIN AF: 0.0765

Gnomad4 NFE AF: 0.0866

Gnomad4 OTH AF: 0.0767

Alfa AF: 0.0826 Hom.: 1351

Bravo AF: 0.0608

TwinsUK AF: 0.0825 AC: 306

ALSPAC AF: 0.0804 AC: 310

ESP6500AA AF: 0.0179 AC: 79

ESP6500EA AF: 0.0917 AC: 789

ExAC AF: 0.0710 AC: 8625

Asia WGS AF: 0.0460 AC: 160 AN: 3478

EpiCase AF: 0.0909

EpiControl AF: 0.0922

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	23
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.20	P;P
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.34
Sift	Benign	0.049	D;D
Sift4G	Benign	0.16	T;T
Polyphen		0.91	P;.
Vest4		0.47
MPC		0.18
ClinPred		0.023	T
GERP RS		4.4
Varity_R		0.37
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2243380; hg19: chr6-117724379; COSMIC: COSV63853037;