rs56090538

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004119.3(FLT3):c.1249A>C(p.Ile417Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,612,380 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0093 ( 31 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 25 hom. )

Consequence

FLT3
NM_004119.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.123

Publications

11 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=0.0076283813).

BP6

Variant 13-28037245-T-G is Benign according to our data. Variant chr13-28037245-T-G is described in ClinVar as Benign. ClinVar VariationId is 134433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00926 (1410/152322) while in subpopulation AFR AF = 0.0313 (1300/41572). AF 95% confidence interval is 0.0299. There are 31 homozygotes in GnomAd4. There are 670 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1410 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT3	NM_004119.3	MANE Select	c.1249A>C	p.Ile417Leu	missense	Exon 10 of 24	NP_004110.2	P36888-1
	FLT3	NR_130706.2		n.1315A>C		non_coding_transcript_exon	Exon 10 of 25

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLT3	ENST00000241453.12	TSL:1 MANE Select	c.1249A>C	p.Ile417Leu	missense	Exon 10 of 24	ENSP00000241453.7	P36888-1
FLT3	ENST00000380987.2	TSL:1	n.1249A>C		non_coding_transcript_exon	Exon 10 of 25	ENSP00000370374.2	E7ER61
FLT3	ENST00000864668.1		c.485-1202A>C		intron	N/A	ENSP00000534727.1

Frequencies

GnomAD3 genomes

AF:

0.00926

AC:

1410

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00261

AC:

656

AN:

251338

AF XY:

0.00194

show subpopulations

Gnomad AFR exome

AF:

0.0332

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000999

AC:

1458

AN:

1460058

Hom.:

Cov.:

AF XY:

0.000880

AC XY:

639

AN XY:

726480

show subpopulations

African (AFR)

AF:

0.0303

AC:

1013

AN:

33422

American (AMR)

AF:

0.00253

AC:

113

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00175

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.000140

AC:

156

AN:

1110498

Other (OTH)

AF:

0.00267

AC:

161

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

133

200

266

333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00926

AC:

1410

AN:

152322

Hom.:

Cov.:

AF XY:

0.00900

AC XY:

670

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0313

AC:

1300

AN:

41572

American (AMR)

AF:

0.00444

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68032

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00380

Hom.:

Bravo

AF:

0.0103

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0322

AC:

142

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00336

AC:

408

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.25

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0076

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.5

PhyloP100

0.12

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.24

REVEL

Benign

0.072

Sift

Benign

0.090

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.26

MutPred

0.32

Gain of catalytic residue at E421 (P = 0.0037)

MVP

0.41

MPC

0.12

ClinPred

0.0053

GERP RS

3.6

Varity_R

0.13

gMVP

0.24

Mutation Taster

=100/0

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over