Variant 6-117310138-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP4_StrongBP6BS2

The NM_001378902.1(ROS1):c.6359G>A(p.Arg2120Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000865 in 1,613,440 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 3 hom. )

Consequence

ROS1
NM_001378902.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.92

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.03419584).

BP6

Variant 6-117310138-C-T is Benign according to our data. Variant chr6-117310138-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 709394.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROS1	NM_001378902.1 linkuse as main transcript	c.6359G>A	p.Arg2120Gln	missense_variant	41/44	ENST00000368507.8	NP_001365831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROS1	ENST00000368507.8 linkuse as main transcript	c.6359G>A	p.Arg2120Gln	missense_variant	41/44	5	NM_001378902.1	ENSP00000357493.3		Q5H8Y1
ROS1	ENST00000368508.7 linkuse as main transcript	c.6377G>A	p.Arg2126Gln	missense_variant	40/43	1		ENSP00000357494.3		P08922

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

157

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.00585

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00165

AC:

415

AN:

251102

Hom.:

AF XY:

0.00186

AC XY:

252

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00523

Gnomad FIN exome

AF:

0.00721

Gnomad NFE exome

AF:

0.000520

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000847

AC:

1238

AN:

1461320

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

730

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000381

Gnomad4 ASJ exome

AF:

0.00230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00472

Gnomad4 FIN exome

AF:

0.00577

Gnomad4 NFE exome

AF:

0.000347

Gnomad4 OTH exome

AF:

0.000861

GnomAD4 genome

AF:

0.00103

AC:

157

AN:

152120

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00456

Gnomad4 FIN

AF:

0.00585

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000718

Hom.:

Bravo

AF:

0.000359

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.00147

AC:

179

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000928

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 12, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

D;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.034

T;T

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.0

M;.

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.6

D;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.87

MVP

0.70

MPC

0.22

ClinPred

0.089

GERP RS

5.5

Varity_R

0.95

gMVP

0.58

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over