rs1057519768

Positions:

• chr13-28028279-T-A
• chr13-28028279-T-C
• chr13-28028279-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The ENST00000241453.12(FLT3):​c.1952A>T​(p.Asp651Val) 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. 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. D651G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLT3 ENST00000241453.12 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.863

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-28028279-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376111.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39254886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLT3	NM_004119.3	c.1952A>T	p.Asp651Val	missense_variant	16/24	ENST00000241453.12	NP_004110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLT3	ENST00000241453.12	c.1952A>T	p.Asp651Val	missense_variant	16/24	1	NM_004119.3	ENSP00000241453	P1
FLT3	ENST00000380987.2	c.1952A>T	p.Asp651Val	missense_variant, NMD_transcript_variant	16/25	1		ENSP00000370374

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.88	L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.026	D
Polyphen		0.99	D
Vest4		0.25
MutPred		0.51		Gain of catalytic residue at D651 (P = 0.0104);
MVP		0.63
MPC		0.68
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.64
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-28602416;