chr13-28015229-A-G

Position:

• chr13-28015229-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004119.3(FLT3):​c.2681T>C​(p.Val894Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FLT3 NM_004119.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30825022).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLT3	NM_004119.3	c.2681T>C	p.Val894Ala	missense_variant	22/24	ENST00000241453.12	NP_004110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLT3	ENST00000241453.12	c.2681T>C	p.Val894Ala	missense_variant	22/24	1	NM_004119.3	ENSP00000241453.7
FLT3	ENST00000380987.2	n.*593T>C		non_coding_transcript_exon_variant	23/25	1		ENSP00000370374.2
FLT3	ENST00000380987.2	n.*593T>C		3_prime_UTR_variant	23/25	1		ENSP00000370374.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459544 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.2681T>C (p.V894A) alteration is located in exon 22 (coding exon 22) of the FLT3 gene. This alteration results from a T to C substitution at nucleotide position 2681, causing the valine (V) at amino acid position 894 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.28	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.29
Sift	Benign	0.035	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0030	B
Vest4		0.31
MutPred		0.54		Gain of catalytic residue at Y889 (P = 0.0011);
MVP		0.76
MPC		0.27
ClinPred		0.93	D
GERP RS		4.1
Varity_R		0.44
gMVP		0.51

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: rs75849452; hg19: chr13-28589366;