NM_004119.3:c.46G>A

Variant names:

• chr13-28070610-C-T
• rs62636526
• NM_004119.3:c.46G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004119.3(FLT3):​c.46G>A​(p.Val16Ile) variant causes a missense, splice region 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. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. V16L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLT3 NM_004119.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.172
• Publications: 5 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3343683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT3	NM_004119.3	c.46G>A	p.Val16Ile	missense_variant, splice_region_variant	Exon 2 of 24	ENST00000241453.12	NP_004110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLT3	ENST00000241453.12	c.46G>A	p.Val16Ile	missense_variant, splice_region_variant	Exon 2 of 24	1	NM_004119.3	ENSP00000241453.7
FLT3	ENST00000380987.2	n.46G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 25	1		ENSP00000370374.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.17
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.29
Sift	Benign	0.47	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.19
MutPred		0.44		Gain of catalytic residue at A19 (P = 2e-04);
MVP		0.66
MPC		0.097
ClinPred		0.42	T
GERP RS		1.1
Varity_R		0.025
gMVP		0.21
Mutation Taster		=90/10	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: rs62636526; hg19: chr13-28644747;