6-117301070-C-T

Variant names:

• chr6-117301070-C-T
• rs529038
• NM_001378902.1:c.6619G>A

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.6619G>A​(p.Asp2207Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,602,860 control chromosomes in the GnomAD database, including 47,546 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2207E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (3241 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44305 hom.)
• Consequence: ROS1 NM_001378902.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.924
• Publications: 42 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=0.0026458502).
• BP6: Variant 6-117301070-C-T is Benign according to our data. Variant chr6-117301070-C-T is described in ClinVar as [Benign]. Clinvar id is 3770413.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROS1	NM_001378902.1	c.6619G>A	p.Asp2207Asn	missense_variant	Exon 43 of 44	ENST00000368507.8	NP_001365831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROS1	ENST00000368507.8	c.6619G>A	p.Asp2207Asn	missense_variant	Exon 43 of 44	5	NM_001378902.1	ENSP00000357493.3
ROS1	ENST00000368508.7	c.6637G>A	p.Asp2213Asn	missense_variant	Exon 42 of 43	1		ENSP00000357494.3

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28437 AN: 151986 Hom.: 3244 Cov.: 32

Gnomad AFR AF: 0.0575

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.180

GnomAD2 exomes AF: 0.203 AC: 49500 AN: 243942 AF XY: 0.205

Gnomad AFR exome AF: 0.0548

Gnomad AMR exome AF: 0.151

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.177

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.213

GnomAD4 exome AF: 0.241 AC: 349551 AN: 1450756 Hom.: 44305 Cov.: 31 AF XY: 0.239 AC XY: 172022 AN XY: 721242

African (AFR) AF: 0.0508 AC: 1688 AN: 33258

American (AMR) AF: 0.155 AC: 6663 AN: 43018

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5296 AN: 26002

East Asian (EAS) AF: 0.165 AC: 6475 AN: 39188

South Asian (SAS) AF: 0.149 AC: 12407 AN: 83502

European-Finnish (FIN) AF: 0.237 AC: 12637 AN: 53276

Middle Eastern (MID) AF: 0.179 AC: 1031 AN: 5758

European-Non Finnish (NFE) AF: 0.262 AC: 289877 AN: 1106784

Other (OTH) AF: 0.225 AC: 13477 AN: 59970

GnomAD4 genome AF: 0.187 AC: 28437 AN: 152104 Hom.: 3241 Cov.: 32 AF XY: 0.184 AC XY: 13670 AN XY: 74346

African (AFR) AF: 0.0575 AC: 2385 AN: 41510

American (AMR) AF: 0.164 AC: 2499 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 759 AN: 3470

East Asian (EAS) AF: 0.173 AC: 897 AN: 5174

South Asian (SAS) AF: 0.160 AC: 769 AN: 4812

European-Finnish (FIN) AF: 0.232 AC: 2454 AN: 10564

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18032 AN: 67978

Other (OTH) AF: 0.178 AC: 375 AN: 2108

Alfa AF: 0.230 Hom.: 14456

Bravo AF: 0.176

TwinsUK AF: 0.249 AC: 925

ALSPAC AF: 0.257 AC: 989

ESP6500AA AF: 0.0688 AC: 303

ESP6500EA AF: 0.259 AC: 2231

ExAC AF: 0.208 AC: 25274

Asia WGS AF: 0.154 AC: 537 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ROS1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.89	L;.
PhyloP100		0.92
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.16
Sift	Benign	0.18	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.0090	B;.
Vest4		0.14
MPC		0.031
ClinPred		0.013	T
GERP RS		3.2
Varity_R		0.25
gMVP		0.32
Mutation Taster		=90/10	polymorphism (auto)

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: rs529038; hg19: chr6-117622233; COSMIC: COSV63850799; COSMIC: COSV63850799;