rs145477191

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001987.5(ETV6):c.602T>C(p.Leu201Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,613,942 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L201L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0049 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0073 ( 49 hom. )

Consequence

ETV6
NM_001987.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:7

Conservation

PhyloP100: 3.14

Publications

23 publications found

Variant links:

Genes affected

ETV6 (HGNC:3495): (ETS variant transcription factor 6) This gene encodes an ETS family transcription factor. The product of this gene contains two functional domains: a N-terminal pointed (PNT) domain that is involved in protein-protein interactions with itself and other proteins, and a C-terminal DNA-binding domain. Gene knockout studies in mice suggest that it is required for hematopoiesis and maintenance of the developing vascular network. This gene is known to be involved in a large number of chromosomal rearrangements associated with leukemia and congenital fibrosarcoma. [provided by RefSeq, Sep 2008]

ETV6 Gene-Disease associations (from GenCC):

thrombocytopenia 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
acute myeloid leukemia
Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics
hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ETV6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007807523).

BP6

Variant 12-11869562-T-C is Benign according to our data. Variant chr12-11869562-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00489 (744/152074) while in subpopulation NFE AF = 0.00799 (543/67984). AF 95% confidence interval is 0.00743. There are 1 homozygotes in GnomAd4. There are 349 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 744 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETV6	NM_001987.5 link	c.602T>C	p.Leu201Pro	missense_variant	Exon 5 of 8	ENST00000396373.9	NP_001978.1	P41212A0A0S2Z3C9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETV6	ENST00000396373.9 link	c.602T>C	p.Leu201Pro	missense_variant	Exon 5 of 8	1	NM_001987.5	ENSP00000379658.3		P41212

Frequencies

GnomAD3 genomes

AF:

0.00489

AC:

743

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00636

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00142

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00799

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00494

AC:

1243

AN:

251426

AF XY:

0.00489

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00448

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.00830

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00731

AC:

10684

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00714

AC XY:

5191

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

33480

American (AMR)

AF:

0.00434

AC:

194

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00107

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00151

AC:

130

AN:

86258

European-Finnish (FIN)

AF:

0.00245

AC:

131

AN:

53412

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00883

AC:

9820

AN:

1111996

Other (OTH)

AF:

0.00538

AC:

325

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

644

1288

1932

2576

3220

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

382

764

1146

1528

1910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00489

AC:

744

AN:

152074

Hom.:

Cov.:

AF XY:

0.00469

AC XY:

349

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41486

American (AMR)

AF:

0.00635

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3466

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.000625

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00142

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00799

AC:

543

AN:

67984

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00665

Hom.:

Bravo

AF:

0.00482

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00499

AC:

606

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00725

EpiControl

AF:

0.00741

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ETV6 p.Leu201Pro variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs145477191) and ClinVar (classified as benign by Genetic Services Laboratory, University of Chicago). The variant was also identified in control databases in 1409 of 282794 chromosomes (6 homozygous) at a frequency of 0.004982 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 1077 of 129130 chromosomes (freq: 0.00834), Other in 36 of 7224 chromosomes (freq: 0.004983), Latino in 163 of 35438 chromosomes (freq: 0.0046), African in 43 of 24960 chromosomes (freq: 0.001723), European (Finnish) in 40 of 25112 chromosomes (freq: 0.001593), South Asian in 41 of 30616 chromosomes (freq: 0.001339) and Ashkenazi Jewish in 9 of 10368 chromosomes (freq: 0.000868), while the variant was not observed in the East Asian population. The p.Leu201 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ETV6: BS1, BS2 -

Jun 06, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

ETV6-related disorder

Benign:1

Jun 05, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Benign:1

Nov 22, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 03, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

Eigen

Benign

0.019

Eigen_PC

Benign

0.099

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0078

MetaSVM

Benign

-0.94

MutationAssessor

Benign

2.0

PhyloP100

3.1

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.5

REVEL

Benign

0.051

Sift

Uncertain

0.0060

Sift4G

Benign

0.093

Polyphen

0.64

Vest4

0.43

MVP

0.11

MPC

0.82

ClinPred

0.019

GERP RS

4.1

Varity_R

0.14

gMVP

0.71

Mutation Taster

=62/38

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over