Genetic Variant FLT3:c.2653+65G>A (chr13-28015525-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_004119.3(FLT3):c.2653+65G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 770,774 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.0012 ( 1 hom., cov: 18)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

FLT3
NM_004119.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.17

Publications

3 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00121 (171/140750) while in subpopulation AFR AF = 0.00412 (159/38622). AF 95% confidence interval is 0.00359. There are 1 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.

BS2

High AC in GnomAd4 at 171 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004119.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT3	NM_004119.3	MANE Select	c.2653+65G>A		intron	N/A	NP_004110.2	P36888-1
	FLT3	NR_130706.2		n.2851+65G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FLT3	ENST00000241453.12	TSL:1 MANE Select	c.2653+65G>A	intron	N/A	ENSP00000241453.7	P36888-1
FLT3	ENST00000380987.2	TSL:1	n.*565+65G>A	intron	N/A	ENSP00000370374.2	E7ER61
FLT3	ENST00000864668.1		c.1828+65G>A	intron	N/A	ENSP00000534727.1

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

170

AN:

140630

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000808

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000527

GnomAD4 exome

AF:

0.000167

AC:

105

AN:

630024

Hom.:

AF XY:

0.000197

AC XY:

AN XY:

339776

show subpopulations

African (AFR)

AF:

0.00475

AC:

AN:

17272

American (AMR)

AF:

0.000184

AC:

AN:

32536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18440

East Asian (EAS)

AF:

0.00

AC:

AN:

35164

South Asian (SAS)

AF:

0.00

AC:

AN:

64334

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2752

European-Non Finnish (NFE)

AF:

0.00000263

AC:

AN:

380832

Other (OTH)

AF:

0.000495

AC:

AN:

32320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00121

AC:

171

AN:

140750

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

AN XY:

67410

show subpopulations

African (AFR)

AF:

0.00412

AC:

159

AN:

38622

American (AMR)

AF:

0.000806

AC:

AN:

13640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3386

East Asian (EAS)

AF:

0.00

AC:

AN:

4502

South Asian (SAS)

AF:

0.00

AC:

AN:

3820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65428

Other (OTH)

AF:

0.000520

AC:

AN:

1922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.561

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

2259

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.6

(source)

DANN

Benign

0.92

PhyloP100

-4.2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over