rs1933437

chr13-28050157-G-Achr13-28050157-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.53 (22664 hom., cov: 33)
  • Exomes 𝑓: 0.62 (279825 hom.)
• Consequence: FLT3 NM_004119.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 3.79

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 134447.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT3	NM_004119.3	c.680C>T	p.Thr227Met	missense_variant	6/24	ENST00000241453.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT3	ENST00000241453.12	c.680C>T	p.Thr227Met	missense_variant	6/24	1	NM_004119.3	P1
FLT3	ENST00000380987.2	c.680C>T	p.Thr227Met	missense_variant, NMD_transcript_variant	6/25	1

Frequencies

GnomAD3 genomes AF: 0.532 AC: 80895 AN: 151936 Hom.: 22648 Cov.: 33

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

GnomAD3 exomes AF: 0.605 AC: 152050 AN: 251366 Hom.: 46973 AF XY: 0.609 AC XY: 82690 AN XY: 135852

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 SAS exome AF: 0.647

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.: 40 AF XY: 0.616 AC XY: 447763 AN XY: 727010

Gnomad4 AFR exome AF: 0.335

Gnomad4 AMR exome AF: 0.607

Gnomad4 ASJ exome AF: 0.585

Gnomad4 EAS exome AF: 0.762

Gnomad4 SAS exome AF: 0.643

Gnomad4 FIN exome AF: 0.609

Gnomad4 NFE exome AF: 0.620

Gnomad4 OTH exome AF: 0.606

GnomAD4 genome AF: 0.532 AC: 80931 AN: 152056 Hom.: 22664 Cov.: 33 AF XY: 0.534 AC XY: 39731 AN XY: 74334

Gnomad4 AFR AF: 0.340

Gnomad4 AMR AF: 0.556

Gnomad4 ASJ AF: 0.586

Gnomad4 EAS AF: 0.764

Gnomad4 SAS AF: 0.663

Gnomad4 FIN AF: 0.595

Gnomad4 NFE AF: 0.604

Gnomad4 OTH AF: 0.535

Alfa AF: 0.595 Hom.: 64416

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:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

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	0.098
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.068
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0000028	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.51	P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.26
Sift	Benign	0.042	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.17
MPC		0.51
ClinPred		0.027	T
GERP RS		3.9
Varity_R		0.046
gMVP		0.55

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

Other links and lift over

dbSNP: rs1933437; hg19: chr13-28624294; COSMIC: COSV54042452;