12-11885968-C-A

Variant names:

• chr12-11885968-C-A
• rs724159945
• NM_001987.5:c.1195C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001987.5(ETV6):​c.1195C>A​(p.Arg399Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R399H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ETV6 NM_001987.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46
• Publications: 20 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), 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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001987.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-11885969-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1175817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETV6	NM_001987.5	c.1195C>A	p.Arg399Ser	missense_variant	Exon 7 of 8	ENST00000396373.9	NP_001978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETV6	ENST00000396373.9	c.1195C>A	p.Arg399Ser	missense_variant	Exon 7 of 8	1	NM_001987.5	ENSP00000379658.3
ETV6	ENST00000266427.3	c.31C>A	p.Arg11Ser	missense_variant	Exon 1 of 2	3		ENSP00000266427.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251438 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Benign	0.44	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.5
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.79		Gain of catalytic residue at R399 (P = 0.0301);
MVP		0.92
MPC		2.9
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		-0.012	Neutral
Varity_R		0.97
gMVP		0.97
Mutation Taster		=1/99	disease causing

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: rs724159945; hg19: chr12-12038902;