rs62636526

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000241453.12(FLT3):c.46G>C(p.Val16Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,596,374 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0022 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 1 hom. )

Consequence

FLT3
ENST00000241453.12 missense, splice_region

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: 0.172

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 made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010351598).

BP6

Variant 13-28070610-C-G is Benign according to our data. Variant chr13-28070610-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 134436.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00224 (341/152232) while in subpopulation AFR AF= 0.00775 (322/41546). AF 95% confidence interval is 0.00705. There are 3 homozygotes in gnomad4. There are 176 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 341 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FLT3	NM_004119.3 linkuse as main transcript	c.46G>C	p.Val16Leu	missense_variant, splice_region_variant	2/24	ENST00000241453.12	NP_004110.2
FLT3	XM_017020486.2 linkuse as main transcript	c.46G>C	p.Val16Leu	missense_variant, splice_region_variant	2/23		XP_016875975.1
FLT3	XM_011535015.3 linkuse as main transcript	c.-12G>C		splice_region_variant, 5_prime_UTR_variant	2/24		XP_011533317.1
FLT3	NR_130706.2 linkuse as main transcript	n.112G>C		splice_region_variant, non_coding_transcript_exon_variant	2/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLT3	ENST00000241453.12 linkuse as main transcript	c.46G>C	p.Val16Leu	missense_variant, splice_region_variant	2/24	1	NM_004119.3	ENSP00000241453	P1	P36888-1
FLT3	ENST00000380987.2 linkuse as main transcript	c.46G>C	p.Val16Leu	missense_variant, splice_region_variant, NMD_transcript_variant	2/25	1		ENSP00000370374

Frequencies

GnomAD3 genomes

AF:

0.00224

AC:

340

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00775

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000594

AC:

147

AN:

247406

Hom.:

AF XY:

0.000515

AC XY:

AN XY:

133968

show subpopulations

Gnomad AFR exome

AF:

0.00814

Gnomad AMR exome

AF:

0.000382

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000219

AC:

316

AN:

1444142

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

139

AN XY:

719536

show subpopulations

Gnomad4 AFR exome

AF:

0.00859

Gnomad4 AMR exome

AF:

0.000361

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.000234

GnomAD4 genome

AF:

0.00224

AC:

341

AN:

152232

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

176

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00775

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000137

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000717

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

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

0.15

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.53

M_CAP

Benign

0.070

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.3

MutationTaster

Benign

0.91

N;N;N

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.14

REVEL

Benign

0.28

Sift

Uncertain

0.017

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.39

MVP

0.53

MPC

0.12

ClinPred

0.042

GERP RS

1.1

Varity_R

0.064

gMVP

0.29

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

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