13-28034336-C-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.1669G>A(p.Val557Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00886 in 1,613,844 control chromosomes in the GnomAD database, including 1,008 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.048 (541 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (467 hom.)
• Consequence: FLT3 NM_004119.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.0310

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=0.0012187362).
• BP6: Variant 13-28034336-C-T is Benign according to our data. Variant chr13-28034336-C-T is described in ClinVar as [Benign]. Clinvar id is 134434.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT3	NM_004119.3	c.1669G>A	p.Val557Ile	missense_variant	13/24	ENST00000241453.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT3	ENST00000241453.12	c.1669G>A	p.Val557Ile	missense_variant	13/24	1	NM_004119.3	P1
FLT3	ENST00000380987.2	c.1669G>A	p.Val557Ile	missense_variant, NMD_transcript_variant	13/25	1

Frequencies

GnomAD3 genomes AF: 0.0476 AC: 7234 AN: 152024 Hom.: 538 Cov.: 33

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0246

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0326

GnomAD3 exomes AF: 0.0128 AC: 3206 AN: 251436 Hom.: 216 AF XY: 0.00923 AC XY: 1254 AN XY: 135886

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.00911

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00109

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00481 AC: 7033 AN: 1461702 Hom.: 467 Cov.: 32 AF XY: 0.00415 AC XY: 3016 AN XY: 727152

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.00153

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000224

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.0477 AC: 7263 AN: 152142 Hom.: 541 Cov.: 33 AF XY: 0.0465 AC XY: 3461 AN XY: 74356

Gnomad4 AFR AF: 0.163

Gnomad4 AMR AF: 0.0245

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.00822 Hom.: 130

Bravo AF: 0.0544

ESP6500AA AF: 0.155 AC: 682

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0153 AC: 1855

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000711

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

Jun 09, 2021

- -

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	0.066
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	7.8
Dann	Benign	0.81
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.043
Sift	Benign	0.66	T
Sift4G	Benign	0.73	T
Polyphen		0.0020	B
Vest4		0.062
MPC		0.097
ClinPred		0.00060	T
GERP RS		2.7
Varity_R		0.019
gMVP		0.40

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: rs35958982; hg19: chr13-28608473; COSMIC: COSV54052276;