chr6-117288553-T-C

Variant names:

• chr6-117288553-T-C
• rs35932630
• NM_001378902.1:c.6965A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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
• Publications: 7 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 -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 GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROS1	NM_001378902.1	c.6965A>G	p.Lys2322Arg	missense_variant	Exon 44 of 44	ENST00000368507.8	NP_001365831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROS1	ENST00000368507.8	c.6965A>G	p.Lys2322Arg	missense_variant	Exon 44 of 44	5	NM_001378902.1	ENSP00000357493.3
ROS1	ENST00000368508.7	c.6983A>G	p.Lys2328Arg	missense_variant	Exon 43 of 43	1		ENSP00000357494.3

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

GnomAD2 exomes AF: 0.00106 AC: 267 AN: 251208 AF XY: 0.000796

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 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

African (AFR) AF: 0.0134 AC: 450 AN: 33478

American (AMR) AF: 0.000716 AC: 32 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000605 AC: 24 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111936

Other (OTH) AF: 0.000679 AC: 41 AN: 60392

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

African (AFR) AF: 0.0142 AC: 591 AN: 41568

American (AMR) AF: 0.00124 AC: 19 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00148 Hom.: 3

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

May 03, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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;.
PhyloP100		0.062
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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs35932630; hg19: chr6-117609716;