13-28052579-C-T

Position:

chr13-28052579-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004119.3(FLT3):c.580G>A(p.Val194Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00469 in 1,613,596 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0042 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 26 hom. )

Consequence

FLT3
NM_004119.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.01

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:

FLT3 (HGNC:):

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=0.00608474).

BP6

Variant 13-28052579-C-T is Benign according to our data. Variant chr13-28052579-C-T is described in ClinVar as [Benign]. Clinvar id is 134446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-28052579-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00424 (646/152300) while in subpopulation NFE AF= 0.00582 (396/68028). AF 95% confidence interval is 0.00535. There are 4 homozygotes in gnomad4. There are 319 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 646 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLT3	NM_004119.3 linkuse as main transcript	c.580G>A	p.Val194Met	missense_variant	5/24	ENST00000241453.12	NP_004110.2	P36888-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLT3	ENST00000241453.12 linkuse as main transcript	c.580G>A	p.Val194Met	missense_variant	5/24	1	NM_004119.3	ENSP00000241453.7		P36888-1
FLT3	ENST00000380987.2 linkuse as main transcript	n.580G>A		non_coding_transcript_exon_variant	5/25	1		ENSP00000370374.2		E7ER61

Frequencies

GnomAD3 genomes

AF:

0.00424

AC:

646

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00480

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00582

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00501

AC:

1259

AN:

251274

Hom.:

AF XY:

0.00522

AC XY:

709

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00290

Gnomad ASJ exome

AF:

0.0261

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00180

Gnomad FIN exome

AF:

0.00453

Gnomad NFE exome

AF:

0.00609

Gnomad OTH exome

AF:

0.00571

GnomAD4 exome

AF:

0.00474

AC:

6921

AN:

1461296

Hom.:

Cov.:

AF XY:

0.00482

AC XY:

3507

AN XY:

726964

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00269

Gnomad4 ASJ exome

AF:

0.0237

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00190

Gnomad4 FIN exome

AF:

0.00427

Gnomad4 NFE exome

AF:

0.00488

Gnomad4 OTH exome

AF:

0.00515

GnomAD4 genome

AF:

0.00424

AC:

646

AN:

152300

Hom.:

Cov.:

AF XY:

0.00428

AC XY:

319

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00405

Gnomad4 ASJ

AF:

0.0248

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00480

Gnomad4 NFE

AF:

0.00582

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00677

Hom.:

Bravo

AF:

0.00400

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00721

AC:

ExAC

AF:

0.00516

AC:

626

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00557

EpiControl

AF:

0.00694

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Benign

-0.014

Eigen_PC

Benign

0.026

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.79

M_CAP

Benign

0.030

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.38

REVEL

Benign

0.22

Sift

Benign

0.072

Sift4G

Benign

0.11

Polyphen

0.95

Vest4

0.27

MVP

0.64

MPC

0.17

ClinPred

0.0065

GERP RS

3.6

Varity_R

0.087

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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