13-28015231-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_004119.3(FLT3):c.2679G>A(p.Pro893=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000447 in 1,611,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: FLT3 NM_004119.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.40

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=-0.66).
• BP6: Variant 13-28015231-C-T is Benign according to our data. Variant chr13-28015231-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 731549.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000743 (113/152140) while in subpopulation AFR AF= 0.00193 (80/41500). AF 95% confidence interval is 0.00159. There are 0 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 113 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT3	NM_004119.3	c.2679G>A	p.Pro893=	synonymous_variant	22/24	ENST00000241453.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT3	ENST00000241453.12	c.2679G>A	p.Pro893=	synonymous_variant	22/24	1	NM_004119.3	P1
FLT3	ENST00000380987.2	c.*591G>A		3_prime_UTR_variant, NMD_transcript_variant	23/25	1

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152022 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000371 AC: 93 AN: 250586 Hom.: 0 AF XY: 0.000332 AC XY: 45 AN XY: 135396

Gnomad AFR exome AF: 0.00179

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000521

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000417 AC: 608 AN: 1459074 Hom.: 0 Cov.: 30 AF XY: 0.000438 AC XY: 318 AN XY: 725982

Gnomad4 AFR exome AF: 0.00192

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.000423

Gnomad4 OTH exome AF: 0.000779

GnomAD4 genome AF: 0.000743 AC: 113 AN: 152140 Hom.: 0 Cov.: 31 AF XY: 0.000806 AC XY: 60 AN XY: 74402

Gnomad4 AFR AF: 0.00193

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000577 Hom.: 0

Bravo AF: 0.000771

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000475

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	2.7
Dann	Benign	0.41

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: rs56300022; hg19: chr13-28589368;