NM_001378902.1:c.6621C>A

Variant names:

• chr6-117301068-G-T
• rs75510639
• NM_001378902.1:c.6621C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001378902.1(ROS1):​c.6621C>A​(p.Asp2207Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,606,976 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2207N) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00033 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: ROS1 NM_001378902.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.265
• Publications: 12 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008882403).
• BP6: Variant 6-117301068-G-T is Benign according to our data. Variant chr6-117301068-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2673077.Status of the report is criteria_provided_single_submitter, 1 stars.

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.6621C>A	p.Asp2207Glu	missense	Exon 43 of 44	NP_001365831.1	Q5H8Y1
	ROS1	NM_002944.3		c.6639C>A	p.Asp2213Glu	missense	Exon 42 of 43	NP_002935.2
	ROS1	NM_001378891.1		c.6627C>A	p.Asp2209Glu	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.6621C>A	p.Asp2207Glu	missense	Exon 43 of 44	ENSP00000357493.3	Q5H8Y1
	ROS1	ENST00000368508.7	TSL:1	c.6639C>A	p.Asp2213Glu	missense	Exon 42 of 43	ENSP00000357494.3	P08922
	ROS1	ENST00000957000.1		c.6666C>A	p.Asp2222Glu	missense	Exon 43 of 44	ENSP00000627059.1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152146 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000643 AC: 158 AN: 245812 AF XY: 0.000624

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00340

Gnomad EAS exome AF: 0.00650

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000214 AC: 311 AN: 1454712 Hom.: 1 Cov.: 31 AF XY: 0.000218 AC XY: 158 AN XY: 723224

African (AFR) AF: 0.0000300 AC: 1 AN: 33328

American (AMR) AF: 0.0000229 AC: 1 AN: 43580

Ashkenazi Jewish (ASJ) AF: 0.00265 AC: 69 AN: 26068

East Asian (EAS) AF: 0.00475 AC: 187 AN: 39372

South Asian (SAS) AF: 0.0000595 AC: 5 AN: 84024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000902 AC: 10 AN: 1109090

Other (OTH) AF: 0.000632 AC: 38 AN: 60116

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152264 Hom.: 1 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74448

African (AFR) AF: 0.00 AC: 0 AN: 41554

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00560 AC: 29 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000149 Hom.: 0

Bravo AF: 0.000442

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000568 AC: 69

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.87
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.49	N
PhyloP100		0.27
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.23
Sift	Benign	0.54	T
Sift4G	Benign	0.38	T
Polyphen		0.0040	B
Vest4		0.10
MutPred		0.11		Loss of helix (P = 0.2022)
MVP		0.32
MPC		0.027
ClinPred		0.018	T
GERP RS		1.1
Varity_R		0.14
gMVP		0.20
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75510639; hg19: chr6-117622231; COSMIC: COSV63856735; COSMIC: COSV63856735;