rs145477191

chr12-11869562-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0073 (49 hom.)
• Consequence: ETV6 NM_001987.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: 3.14

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 743 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETV6	NM_001987.5	c.602T>C	p.Leu201Pro	missense_variant	5/8	ENST00000396373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETV6	ENST00000396373.9	c.602T>C	p.Leu201Pro	missense_variant	5/8	1	NM_001987.5	P1

Frequencies

GnomAD3 genomes AF: 0.00489 AC: 743 AN: 151956 Hom.: 1 Cov.: 31

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

GnomAD3 exomes AF: 0.00494 AC: 1243 AN: 251426 Hom.: 5 AF XY: 0.00489 AC XY: 664 AN XY: 135886

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 SAS exome AF: 0.00134

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.: 49 Cov.: 31 AF XY: 0.00714 AC XY: 5191 AN XY: 727238

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00434

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00151

Gnomad4 FIN exome AF: 0.00245

Gnomad4 NFE exome AF: 0.00883

Gnomad4 OTH exome AF: 0.00538

GnomAD4 genome AF: 0.00489 AC: 744 AN: 152074 Hom.: 1 Cov.: 31 AF XY: 0.00469 AC XY: 349 AN XY: 74346

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00635

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000625

Gnomad4 FIN AF: 0.00142

Gnomad4 NFE AF: 0.00799

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00692 Hom.: 6

Bravo AF: 0.00482

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00499 AC: 606

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00741

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2022	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	ETV6: BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 22, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.019
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.051
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.093	T
Polyphen		0.64	P
Vest4		0.43
MVP		0.11
MPC		0.82
ClinPred		0.019	T
GERP RS		4.1
Varity_R		0.14
gMVP		0.71

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

Other links and lift over

dbSNP: rs145477191; hg19: chr12-12022496; COSMIC: COSV67148666;