Variant chr13-28014453-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004119.3(FLT3):c.2858C>A(p.Ala953Glu) 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. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FLT3
NM_004119.3 missense, splice_region

Scores

Splicing: ADA: 0.001742

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.20

Variant links:

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]

FLT3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14041874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT3	NM_004119.3 link	c.2858C>A	p.Ala953Glu	missense_variant, splice_region_variant	Exon 23 of 24	ENST00000241453.12	NP_004110.2	P36888-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FLT3	ENST00000241453.12 link	c.2858C>A	p.Ala953Glu	missense_variant, splice_region_variant	Exon 23 of 24	1	NM_004119.3	ENSP00000241453.7	P36888-1
FLT3	ENST00000380987.2 link	n.*770C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 24 of 25	1		ENSP00000370374.2	E7ER61
FLT3	ENST00000380987.2 link	n.*770C>A		3_prime_UTR_variant	Exon 24 of 25	1		ENSP00000370374.2	E7ER61
FLT3	ENST00000469894.1 link	n.60C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1453336

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723538

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.22

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.57

M_CAP

Benign

0.039

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.080

REVEL

Benign

0.20

Sift

Benign

0.23

Sift4G

Benign

0.34

Polyphen

0.0090

Vest4

0.29

MutPred

0.40

Gain of catalytic residue at N957 (P = 0.0024);

MVP

0.34

MPC

0.20

ClinPred

0.39

GERP RS

4.9

Varity_R

0.15

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0017

dbscSNV1_RF

Benign

0.098

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over