6-117329351-T-C

Variant names:

• chr6-117329351-T-C
• rs149390376
• NM_001378902.1:c.5326A>G

Variant summary

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

The NM_001378902.1(ROS1):​c.5326A>G​(p.Thr1776Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000444 in 1,531,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1776P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: ROS1 NM_001378902.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.566
• 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=0.04587972).

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.5326A>G	p.Thr1776Ala	missense	Exon 33 of 44	NP_001365831.1	Q5H8Y1
	ROS1	NM_002944.3		c.5344A>G	p.Thr1782Ala	missense	Exon 32 of 43	NP_002935.2
	ROS1	NM_001378891.1		c.5332A>G	p.Thr1778Ala	missense	Exon 33 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.5326A>G	p.Thr1776Ala	missense	Exon 33 of 44	ENSP00000357493.3	Q5H8Y1
	ROS1	ENST00000368508.7	TSL:1	c.5344A>G	p.Thr1782Ala	missense	Exon 32 of 43	ENSP00000357494.3	P08922
	ENSG00000282218	ENST00000467125.1	TSL:2	c.548-7957A>G		intron	N/A	ENSP00000487717.1	A0A0J9YVX5

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000561 AC: 14 AN: 249428 AF XY: 0.0000519

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000879

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000972

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000406 AC: 56 AN: 1379312 Hom.: 0 Cov.: 23 AF XY: 0.0000478 AC XY: 33 AN XY: 691046

African (AFR) AF: 0.00 AC: 0 AN: 31672

American (AMR) AF: 0.0000451 AC: 2 AN: 44312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25632

East Asian (EAS) AF: 0.00 AC: 0 AN: 39202

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.0000482 AC: 50 AN: 1038194

Other (OTH) AF: 0.0000521 AC: 3 AN: 57592

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74500

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.6
DANN	Benign	0.78
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.57
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.079
Sift	Benign	0.56	T
Sift4G	Benign	0.21	T
Polyphen		0.0020	B
Vest4		0.12
MVP		0.040
MPC		0.026
ClinPred		0.021	T
GERP RS		-1.9
Varity_R		0.046
gMVP		0.34
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs149390376; hg19: chr6-117650514;