13-28004116-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004119.3(FLT3):c.2918G>A(p.Arg973Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000351 in 1,614,006 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: FLT3 NM_004119.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.540

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005397469).
• BP6: Variant 13-28004116-C-T is Benign according to our data. Variant chr13-28004116-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 134440.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00188 (286/152192) while in subpopulation AFR AF= 0.00648 (269/41532). AF 95% confidence interval is 0.00584. There are 4 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 285 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT3	NM_004119.3	c.2918G>A	p.Arg973Gln	missense_variant	24/24	ENST00000241453.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT3	ENST00000241453.12	c.2918G>A	p.Arg973Gln	missense_variant	24/24	1	NM_004119.3	P1
FLT3	ENST00000380987.2	c.*830G>A		3_prime_UTR_variant, NMD_transcript_variant	25/25	1
FLT3	ENST00000469894.1	n.305G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152074 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000501 AC: 126 AN: 251472 Hom.: 0 AF XY: 0.000441 AC XY: 60 AN XY: 135912

Gnomad AFR exome AF: 0.00714

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000192 AC: 280 AN: 1461814 Hom.: 1 Cov.: 31 AF XY: 0.000169 AC XY: 123 AN XY: 727200

Gnomad4 AFR exome AF: 0.00741

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152192 Hom.: 4 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74398

Gnomad4 AFR AF: 0.00648

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000301 Hom.: 0

Bravo AF: 0.00216

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000593 AC: 72

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 26, 2018

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	6.1
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.068
Sift	Uncertain	0.022	D
Sift4G	Benign	0.60	T
Polyphen		0.0020	B
Vest4		0.029
MVP		0.38
MPC		0.14
ClinPred		0.016	T
GERP RS		0.44
Varity_R		0.049
gMVP		0.45

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: rs144397269; hg19: chr13-28578253;