13-28004076-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_004119.3(FLT3):c.2958G>A(p.Pro986=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00694 in 1,613,984 control chromosomes in the GnomAD database, including 545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.036 (288 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (257 hom.)
• Consequence: FLT3 NM_004119.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.388

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 13-28004076-C-T is Benign according to our data. Variant chr13-28004076-C-T is described in ClinVar as [Benign]. Clinvar id is 1178009.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.388 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT3	NM_004119.3	c.2958G>A	p.Pro986=	synonymous_variant	24/24	ENST00000241453.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT3	ENST00000241453.12	c.2958G>A	p.Pro986=	synonymous_variant	24/24	1	NM_004119.3	P1
FLT3	ENST00000380987.2	c.*870G>A		3_prime_UTR_variant, NMD_transcript_variant	25/25	1
FLT3	ENST00000469894.1	n.345G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5461 AN: 152044 Hom.: 287 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.00920 AC: 2314 AN: 251486 Hom.: 106 AF XY: 0.00659 AC XY: 896 AN XY: 135914

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.00844

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000765

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00392 AC: 5735 AN: 1461822 Hom.: 257 Cov.: 31 AF XY: 0.00341 AC XY: 2478 AN XY: 727214

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.00944

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000559

Gnomad4 OTH exome AF: 0.00871

GnomAD4 genome AF: 0.0359 AC: 5469 AN: 152162 Hom.: 288 Cov.: 32 AF XY: 0.0348 AC XY: 2590 AN XY: 74396

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0187

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0116 Hom.: 60

Bravo AF: 0.0418

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00101

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 09, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.67
Dann	Benign	0.54

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: rs56027115; hg19: chr13-28578213;