13-28034336-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004119.3(FLT3):c.1669G>A(p.Val557Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00886 in 1,613,844 control chromosomes in the GnomAD database, including 1,008 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.048 ( 541 hom., cov: 33)

Exomes 𝑓: 0.0048 ( 467 hom. )

Consequence

FLT3
NM_004119.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: -0.0310

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012187362).

BP6

Variant 13-28034336-C-T is Benign according to our data. Variant chr13-28034336-C-T is described in ClinVar as [Benign]. Clinvar id is 134434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT3	NM_004119.3 link	c.1669G>A	p.Val557Ile	missense_variant	Exon 13 of 24	ENST00000241453.12	NP_004110.2	P36888-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLT3	ENST00000241453.12 link	c.1669G>A	p.Val557Ile	missense_variant	Exon 13 of 24	1	NM_004119.3	ENSP00000241453.7		P36888-1
FLT3	ENST00000380987.2 link	n.1669G>A		non_coding_transcript_exon_variant	Exon 13 of 25	1		ENSP00000370374.2		E7ER61

Frequencies

GnomAD3 genomes

AF:

0.0476

AC:

7234

AN:

152024

Hom.:

538

Cov.:

show subpopulations

Gnomad AFR

AF:

0.163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0246

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.0326

GnomAD3 exomes

AF:

0.0128

AC:

3206

AN:

251436

Hom.:

216

AF XY:

0.00923

AC XY:

1254

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.166

Gnomad AMR exome

AF:

0.00911

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.00109

Gnomad SAS exome

AF:

0.00140

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000528

Gnomad OTH exome

AF:

0.00750

GnomAD4 exome

AF:

0.00481

AC:

7033

AN:

1461702

Hom.:

467

Cov.:

AF XY:

0.00415

AC XY:

3016

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.161

Gnomad4 AMR exome

AF:

0.0102

Gnomad4 ASJ exome

AF:

0.00207

Gnomad4 EAS exome

AF:

0.000479

Gnomad4 SAS exome

AF:

0.00153

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000224

Gnomad4 OTH exome

AF:

0.0114

GnomAD4 genome

AF:

0.0477

AC:

7263

AN:

152142

Hom.:

541

Cov.:

AF XY:

0.0465

AC XY:

3461

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.163

Gnomad4 AMR

AF:

0.0245

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.0322

Alfa

AF:

0.00822

Hom.:

130

Bravo

AF:

0.0544

ESP6500AA

AF:

0.155

AC:

682

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.0153

AC:

1855

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.8

DANN

Benign

0.81

DEOGEN2

Benign

0.23

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0012

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.61

PrimateAI

Benign

0.31

PROVEAN

Benign

0.12

REVEL

Benign

0.043

Sift

Benign

0.66

Sift4G

Benign

0.73

Polyphen

0.0020

Vest4

0.062

MPC

0.097

ClinPred

0.00060

GERP RS

2.7

Varity_R

0.019

gMVP

0.40

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over