rs145477191

Variant names:

• chr12-11869562-T-C
• rs145477191
• NM_001987.5:c.602T>C

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: 3.14
• Publications: 23 publications found

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), ClinGen, Ambry Genetics
• 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

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001987.5. 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
	ETV6	NM_001987.5	MANE Select	c.602T>C	p.Leu201Pro	missense	Exon 5 of 8	NP_001978.1	P41212
	ETV6	NM_001413913.1		c.599T>C	p.Leu200Pro	missense	Exon 5 of 8	NP_001400842.1
	ETV6	NM_001413914.1		c.575T>C	p.Leu192Pro	missense	Exon 6 of 9	NP_001400843.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETV6	ENST00000396373.9	TSL:1 MANE Select	c.602T>C	p.Leu201Pro	missense	Exon 5 of 8	ENSP00000379658.3	P41212
	ETV6	ENST00000904922.1		c.599T>C	p.Leu200Pro	missense	Exon 5 of 8	ENSP00000574981.1
	ETV6	ENST00000904923.1		c.467T>C	p.Leu156Pro	missense	Exon 4 of 7	ENSP00000574982.1

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

GnomAD2 exomes AF: 0.00494 AC: 1243 AN: 251426 AF XY: 0.00489

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

African (AFR) AF: 0.00146 AC: 49 AN: 33480

American (AMR) AF: 0.00434 AC: 194 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 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: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00883 AC: 9820 AN: 1111996

Other (OTH) AF: 0.00538 AC: 325 AN: 60394

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

African (AFR) AF: 0.00161 AC: 67 AN: 41486

American (AMR) AF: 0.00635 AC: 97 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.000625 AC: 3 AN: 4802

European-Finnish (FIN) AF: 0.00142 AC: 15 AN: 10578

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

European-Non Finnish (NFE) AF: 0.00799 AC: 543 AN: 67984

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00665 Hom.: 8

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	1	ETV6-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.1
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
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

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