13-28050157-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004119.3(FLT3):c.680C>T(p.Thr227Met) variant causes a missense change. The variant allele was found at a frequency of 0.608 in 1,613,410 control chromosomes in the GnomAD database, including 302,489 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 22664 hom., cov: 33)

Exomes 𝑓: 0.62 ( 279825 hom. )

Consequence

FLT3
NM_004119.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.79

Publications

101 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.793968E-6).

BP6

Variant 13-28050157-G-A is Benign according to our data. Variant chr13-28050157-G-A is described in ClinVar as Benign. ClinVar VariationId is 134447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004119.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT3	NM_004119.3	MANE Select	c.680C>T	p.Thr227Met	missense	Exon 6 of 24	NP_004110.2
	FLT3	NR_130706.2		n.746C>T		non_coding_transcript_exon	Exon 6 of 25

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT3	ENST00000241453.12	TSL:1 MANE Select	c.680C>T	p.Thr227Met	missense	Exon 6 of 24	ENSP00000241453.7
	FLT3	ENST00000380987.2	TSL:1	n.680C>T		non_coding_transcript_exon	Exon 6 of 25	ENSP00000370374.2

Frequencies

GnomAD3 genomes

AF:

0.532

AC:

80895

AN:

151936

Hom.:

22648

Cov.:

show subpopulations

Gnomad AFR

AF:

0.341

Gnomad AMI

AF:

0.567

Gnomad AMR

AF:

0.555

Gnomad ASJ

AF:

0.586

Gnomad EAS

AF:

0.764

Gnomad SAS

AF:

0.663

Gnomad FIN

AF:

0.595

Gnomad MID

AF:

0.462

Gnomad NFE

AF:

0.604

Gnomad OTH

AF:

0.530

GnomAD2 exomes

AF:

0.605

AC:

152050

AN:

251366

AF XY:

0.609

show subpopulations

Gnomad AFR exome

AF:

0.335

Gnomad AMR exome

AF:

0.615

Gnomad ASJ exome

AF:

0.576

Gnomad EAS exome

AF:

0.764

Gnomad FIN exome

AF:

0.602

Gnomad NFE exome

AF:

0.607

Gnomad OTH exome

AF:

0.594

GnomAD4 exome

AF:

0.616

AC:

900045

AN:

1461354

Hom.:

279825

Cov.:

AF XY:

0.616

AC XY:

447763

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.335

AC:

11219

AN:

33468

American (AMR)

AF:

0.607

AC:

27155

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.585

AC:

15270

AN:

26118

East Asian (EAS)

AF:

0.762

AC:

30253

AN:

39686

South Asian (SAS)

AF:

0.643

AC:

55482

AN:

86240

European-Finnish (FIN)

AF:

0.609

AC:

32531

AN:

53398

Middle Eastern (MID)

AF:

0.472

AC:

2725

AN:

5768

European-Non Finnish (NFE)

AF:

0.620

AC:

688853

AN:

1111590

Other (OTH)

AF:

0.606

AC:

36557

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

16388

32777

49165

65554

81942

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18550

37100

55650

74200

92750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.532

AC:

80931

AN:

152056

Hom.:

22664

Cov.:

AF XY:

0.534

AC XY:

39731

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.340

AC:

14117

AN:

41468

American (AMR)

AF:

0.556

AC:

8494

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.586

AC:

2032

AN:

3470

East Asian (EAS)

AF:

0.764

AC:

3951

AN:

5174

South Asian (SAS)

AF:

0.663

AC:

3192

AN:

4812

European-Finnish (FIN)

AF:

0.595

AC:

6289

AN:

10566

Middle Eastern (MID)

AF:

0.456

AC:

134

AN:

294

European-Non Finnish (NFE)

AF:

0.604

AC:

41077

AN:

67976

Other (OTH)

AF:

0.535

AC:

1129

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1857

3714

5570

7427

9284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

720

1440

2160

2880

3600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.587

Hom.:

127495

Bravo

AF:

0.525

TwinsUK

AF:

0.610

AC:

2262

ALSPAC

AF:

0.617

AC:

2379

ESP6500AA

AF:

0.343

AC:

1513

ESP6500EA

AF:

0.615

AC:

5288

ExAC

AF:

0.599

AC:

72680

Asia WGS

AF:

0.659

AC:

2289

AN:

3478

EpiCase

AF:

0.592

EpiControl

AF:

0.594

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Benign

-0.068

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0000028

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.90

PhyloP100

3.8

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.4

REVEL

Benign

0.26

Sift

Benign

0.042

Sift4G

Benign

0.10

Polyphen

1.0

Vest4

0.17

MPC

0.51

ClinPred

0.027

GERP RS

3.9

Varity_R

0.046

gMVP

0.55

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over