rs138003347

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.2888C>T(p.Ser963Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000377 in 1,613,884 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 2 hom. )

Consequence

FLT3
NM_004119.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.810

Publications

14 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=0.05001706).

BP6

Variant 13-28004146-G-A is Benign according to our data. Variant chr13-28004146-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 134438.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 = 0.00025 (38/152092) while in subpopulation NFE AF = 0.000426 (29/68012). AF 95% confidence interval is 0.000304. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT3	NM_004119.3 link	c.2888C>T	p.Ser963Leu	missense_variant	Exon 24 of 24	ENST00000241453.12	NP_004110.2	P36888-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FLT3	ENST00000241453.12 link	c.2888C>T	p.Ser963Leu	missense_variant	Exon 24 of 24	1	NM_004119.3	ENSP00000241453.7	P36888-1
FLT3	ENST00000380987.2 link	n.*800C>T		non_coding_transcript_exon_variant	Exon 25 of 25	1		ENSP00000370374.2	E7ER61
FLT3	ENST00000380987.2 link	n.*800C>T		3_prime_UTR_variant	Exon 25 of 25	1		ENSP00000370374.2	E7ER61
FLT3	ENST00000469894.1 link	n.275C>T		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000247

AC:

AN:

251412

AF XY:

0.000287

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000390

AC:

570

AN:

1461792

Hom.:

Cov.:

AF XY:

0.000419

AC XY:

305

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33478

American (AMR)

AF:

0.000179

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000580

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.000446

AC:

496

AN:

1111964

Other (OTH)

AF:

0.000149

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000250

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68012

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000473

Hom.:

Bravo

AF:

0.000257

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000533

ClinVar

Significance: Likely 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

0.069

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.49

CADD

Benign

8.4

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.36

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.50

M_CAP

Benign

0.027

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.76

PhyloP100

0.81

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.1

REVEL

Benign

0.083

Sift

Benign

0.054

Sift4G

Benign

0.11

Polyphen

0.0050

Vest4

0.11

MVP

0.30

MPC

0.11

ClinPred

0.019

GERP RS

0.78

Varity_R

0.040

gMVP

0.34

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over