13-28034336-C-G

Position:

• chr13-28034336-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004119.3(FLT3):​c.1669G>C​(p.Val557Leu) 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. 16/21 in silico tools predict 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. V557I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLT3 NM_004119.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0310

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.063271224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLT3	NM_004119.3	c.1669G>C	p.Val557Leu	missense_variant	13/24	ENST00000241453.12	NP_004110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLT3	ENST00000241453.12	c.1669G>C	p.Val557Leu	missense_variant	13/24	1	NM_004119.3	ENSP00000241453	P1
FLT3	ENST00000380987.2	c.1669G>C	p.Val557Leu	missense_variant, NMD_transcript_variant	13/25	1		ENSP00000370374

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.4
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.52	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.049
Sift	Benign	0.12	T
Sift4G	Benign	0.41	T
Polyphen		0.0040	B
Vest4		0.18
MutPred		0.31		Gain of catalytic residue at L553 (P = 0);
MVP		0.28
MPC		0.13
ClinPred		0.074	T
GERP RS		2.7
Varity_R		0.030
gMVP		0.51

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: chr13-28608473;