6-117318226-C-A

Variant names:

• chr6-117318226-C-A
• rs139620900
• NM_001378902.1:c.5949G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001378902.1(ROS1):​c.5949G>T​(p.Gln1983His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,612,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ROS1 NM_001378902.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.485
• Publications: 4 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

ENSG00000282218 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06498709).

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.5949G>T	p.Gln1983His	missense	Exon 38 of 44	NP_001365831.1	Q5H8Y1
	ROS1	NM_002944.3		c.5967G>T	p.Gln1989His	missense	Exon 37 of 43	NP_002935.2
	ROS1	NM_001378891.1		c.5955G>T	p.Gln1985His	missense	Exon 38 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.5949G>T	p.Gln1983His	missense	Exon 38 of 44	ENSP00000357493.3	Q5H8Y1
	ROS1	ENST00000368508.7	TSL:1	c.5967G>T	p.Gln1989His	missense	Exon 37 of 43	ENSP00000357494.3	P08922
	ENSG00000282218	ENST00000467125.1	TSL:2	c.915G>T	p.Gln305His	missense	Exon 7 of 7	ENSP00000487717.1	A0A0J9YVX5

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000359 AC: 9 AN: 250474 AF XY: 0.00000739

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460688 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726668

African (AFR) AF: 0.000150 AC: 5 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111268

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74316

African (AFR) AF: 0.000724 AC: 30 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000659 Hom.: 0

Bravo AF: 0.000227

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.48
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.29
Sift	Benign	0.12	T
Sift4G	Benign	0.18	T
Polyphen		0.42	B
Vest4		0.34
MutPred		0.33		Gain of ubiquitination at K1991 (P = 0.0817)
MVP		0.36
MPC		0.032
ClinPred		0.089	T
GERP RS		2.8
Varity_R		0.37
gMVP		0.30
Mutation Taster		=47/53	disease causing

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: rs139620900; hg19: chr6-117639389;