13-28018409-T-C

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.2541+58A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,594,688 control chromosomes in the GnomAD database, including 41,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (3568 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37479 hom.)
• Consequence: FLT3 NM_004119.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.465

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 (BayesDel_noAF=-0.75).
• BP6: Variant 13-28018409-T-C is Benign according to our data. Variant chr13-28018409-T-C is described in ClinVar as [Benign]. Clinvar id is 1245510.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT3	NM_004119.3	c.2541+58A>G		intron_variant		ENST00000241453.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT3	ENST00000241453.12	c.2541+58A>G		intron_variant		1	NM_004119.3	P1
FLT3	ENST00000380987.2	c.*453+58A>G		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31399 AN: 152078 Hom.: 3567 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.222

GnomAD3 exomes AF: 0.238 AC: 58413 AN: 245906 Hom.: 7661 AF XY: 0.247 AC XY: 32930 AN XY: 133162

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.247

Gnomad SAS exome AF: 0.397

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.219 AC: 316554 AN: 1442492 Hom.: 37479 Cov.: 26 AF XY: 0.226 AC XY: 162079 AN XY: 716656

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.252

Gnomad4 ASJ exome AF: 0.219

Gnomad4 EAS exome AF: 0.302

Gnomad4 SAS exome AF: 0.397

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.206

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.206 AC: 31422 AN: 152196 Hom.: 3568 Cov.: 32 AF XY: 0.211 AC XY: 15690 AN XY: 74410

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.260

Gnomad4 ASJ AF: 0.213

Gnomad4 EAS AF: 0.265

Gnomad4 SAS AF: 0.402

Gnomad4 FIN AF: 0.180

Gnomad4 NFE AF: 0.216

Gnomad4 OTH AF: 0.222

Alfa AF: 0.219 Hom.: 998

Bravo AF: 0.201

Asia WGS AF: 0.313 AC: 1085 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	6.9
Dann	Benign	0.75

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: rs17086226; hg19: chr13-28592546; COSMIC: COSV54044799; COSMIC: COSV54044799;