13-28049450-C-T

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.970G>A(p.Asp324Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,613,454 control chromosomes in the GnomAD database, including 423 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D324D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 19 hom., cov: 33)

Exomes 𝑓: 0.022 ( 404 hom. )

Consequence

FLT3
NM_004119.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.0930

Publications

39 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=0.0031169355).

BP6

Variant 13-28049450-C-T is Benign according to our data. Variant chr13-28049450-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 134451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0158 (2402/151888) while in subpopulation NFE AF = 0.0243 (1651/67916). AF 95% confidence interval is 0.0233. There are 19 homozygotes in GnomAd4. There are 1103 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2402 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.970G>A	p.Asp324Asn	missense	Exon 8 of 24	NP_004110.2	P36888-1
	FLT3	NR_130706.2		n.1036G>A		non_coding_transcript_exon	Exon 8 of 25

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLT3	ENST00000241453.12	TSL:1 MANE Select	c.970G>A	p.Asp324Asn	missense	Exon 8 of 24	ENSP00000241453.7	P36888-1
FLT3	ENST00000380987.2	TSL:1	n.970G>A		non_coding_transcript_exon	Exon 8 of 25	ENSP00000370374.2	E7ER61
FLT3	ENST00000864668.1		c.484+7897G>A		intron	N/A	ENSP00000534727.1

Frequencies

GnomAD3 genomes

AF:

0.0158

AC:

2401

AN:

151768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00410

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.0136

Gnomad ASJ

AF:

0.0407

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00793

Gnomad FIN

AF:

0.0136

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0243

Gnomad OTH

AF:

0.0192

GnomAD2 exomes

AF:

0.0172

AC:

4328

AN:

251354

AF XY:

0.0177

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.0107

Gnomad ASJ exome

AF:

0.0429

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0135

Gnomad NFE exome

AF:

0.0246

Gnomad OTH exome

AF:

0.0214

GnomAD4 exome

AF:

0.0218

AC:

31838

AN:

1461566

Hom.:

404

Cov.:

AF XY:

0.0215

AC XY:

15632

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.00424

AC:

142

AN:

33478

American (AMR)

AF:

0.0109

AC:

486

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0410

AC:

1071

AN:

26128

East Asian (EAS)

AF:

0.000101

AC:

AN:

39690

South Asian (SAS)

AF:

0.00870

AC:

750

AN:

86230

European-Finnish (FIN)

AF:

0.0158

AC:

846

AN:

53390

Middle Eastern (MID)

AF:

0.0208

AC:

120

AN:

5768

European-Non Finnish (NFE)

AF:

0.0243

AC:

27018

AN:

1111772

Other (OTH)

AF:

0.0232

AC:

1401

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

1529

3057

4586

6114

7643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1014

2028

3042

4056

5070

<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:

0.0158

AC:

2402

AN:

151888

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1103

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.00408

AC:

169

AN:

41376

American (AMR)

AF:

0.0136

AC:

208

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.0407

AC:

141

AN:

3464

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.00793

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.0136

AC:

144

AN:

10612

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0243

AC:

1651

AN:

67916

Other (OTH)

AF:

0.0190

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

126

252

378

504

630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0215

Hom.:

119

Bravo

AF:

0.0153

TwinsUK

AF:

0.0232

AC:

ALSPAC

AF:

0.0215

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0235

AC:

202

ExAC

AF:

0.0165

AC:

2005

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0261

EpiControl

AF:

0.0242

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

FLT3-related disorder (1)

not provided (1)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.39

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

PhyloP100

-0.093

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.041

Sift

Benign

0.15

Sift4G

Benign

0.24

Polyphen

0.0050

Vest4

0.12

MPC

0.13

ClinPred

0.0084

GERP RS

0.90

Varity_R

0.20

gMVP

0.46

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over