rs35602083

Positions:

• chr13-28049450-C-A
• chr13-28049450-C-G
• chr13-28049450-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004119.3(FLT3):​c.970G>T​(p.Asp324Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D324N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FLT3 NM_004119.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0930

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT3	NM_004119.3	c.970G>T	p.Asp324Tyr	missense_variant	8/24	ENST00000241453.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT3	ENST00000241453.12	c.970G>T	p.Asp324Tyr	missense_variant	8/24	1	NM_004119.3	P1
FLT3	ENST00000380987.2	c.970G>T	p.Asp324Tyr	missense_variant, NMD_transcript_variant	8/25	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461672 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727138

Gnomad4 AFR exome AF: 0.0000299

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.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Benign	0.076
Sift	Benign	0.039	D
Sift4G	Uncertain	0.060	T
Polyphen		0.16	B
Vest4		0.70
MutPred		0.56		Gain of catalytic residue at R322 (P = 0);
MVP		0.39
MPC		0.36
ClinPred		0.79	D
GERP RS		0.90
Varity_R		0.29
gMVP		0.66

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: rs35602083; hg19: chr13-28623587;