6-117288553-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001378902.1(ROS1):c.6965A>G(p.Lys2322Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000736 in 1,614,120 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (3 hom.)
• Consequence: ROS1 NM_001378902.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0620

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018203557).
• BP6: Variant 6-117288553-T-C is Benign according to our data. Variant chr6-117288553-T-C is described in ClinVar as [Benign]. Clinvar id is 782476.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROS1	NM_001378902.1	c.6965A>G	p.Lys2322Arg	missense_variant	44/44	ENST00000368507.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROS1	ENST00000368507.8	c.6965A>G	p.Lys2322Arg	missense_variant	44/44	5	NM_001378902.1	P1
ROS1	ENST00000368508.7	c.6983A>G	p.Lys2328Arg	missense_variant	43/43	1

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 618 AN: 152206 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00106 AC: 267 AN: 251208 Hom.: 2 AF XY: 0.000796 AC XY: 108 AN XY: 135762

Gnomad AFR exome AF: 0.0133

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00130

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000390 AC: 570 AN: 1461794 Hom.: 3 Cov.: 32 AF XY: 0.000351 AC XY: 255 AN XY: 727194

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.00406 AC: 618 AN: 152326 Hom.: 4 Cov.: 33 AF XY: 0.00413 AC XY: 308 AN XY: 74490

Gnomad4 AFR AF: 0.0142

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000716 Hom.: 0

Bravo AF: 0.00453

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00140 AC: 170

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 03, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	8.2
Dann	Benign	0.90
DEOGEN2	Benign	0.081	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.15
Sift	Benign	0.64	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.15	B;.
Vest4		0.044
MVP		0.18
MPC		0.023
ClinPred		0.0021	T
GERP RS		-0.28
Varity_R		0.027
gMVP		0.13

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: rs35932630; hg19: chr6-117609716; COSMIC: COSV100876541;