rs1057519765

chr13-28027236-T-Achr13-28027236-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_004119.3(FLT3):c.2059A>T(p.Ile687Phe) 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 benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLT3 NM_004119.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0480

Genes affected

FLT3 (HGNC:3765): (fms related receptor tyrosine kinase 3) This gene encodes a class III receptor tyrosine kinase that regulates hematopoiesis. This receptor is activated by binding of the fms-related tyrosine kinase 3 ligand to the extracellular domain, which induces homodimer formation in the plasma membrane leading to autophosphorylation of the receptor. The activated receptor kinase subsequently phosphorylates and activates multiple cytoplasmic effector molecules in pathways involved in apoptosis, proliferation, and differentiation of hematopoietic cells in bone marrow. Mutations that result in the constitutive activation of this receptor result in acute myeloid leukemia and acute lymphoblastic leukemia. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-28027236-T-A is Pathogenic according to our data. Variant chr13-28027236-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376107.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38242617).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT3	NM_004119.3	c.2059A>T	p.Ile687Phe	missense_variant	17/24	ENST00000241453.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT3	ENST00000241453.12	c.2059A>T	p.Ile687Phe	missense_variant	17/24	1	NM_004119.3	P1
FLT3	ENST00000380987.2	c.2059A>T	p.Ile687Phe	missense_variant, NMD_transcript_variant	17/25	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acute myeloid leukemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.72	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.46
Sift	Benign	0.033	D
Sift4G	Uncertain	0.024	D
Polyphen		0.095	B
Vest4		0.51
MutPred		0.55		Gain of catalytic residue at E692 (P = 0);
MVP		0.78
MPC		0.61
ClinPred		0.88	D
GERP RS		-5.6
Varity_R		0.47
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1057519765; hg19: chr13-28601373;