rs62636526

chr13-28070610-C-Gchr13-28070610-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.46G>C(p.Val16Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,596,374 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: FLT3 NM_004119.3 missense, splice_region
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.172

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=0.010351598).
• BP6: Variant 13-28070610-C-G is Benign according to our data. Variant chr13-28070610-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 134436.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00224 (341/152232) while in subpopulation AFR AF= 0.00775 (322/41546). AF 95% confidence interval is 0.00705. There are 3 homozygotes in gnomad4. There are 176 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 340 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT3	NM_004119.3	c.46G>C	p.Val16Leu	missense_variant, splice_region_variant	2/24	ENST00000241453.12
FLT3	XM_017020486.2	c.46G>C	p.Val16Leu	missense_variant, splice_region_variant	2/23
FLT3	XM_011535015.3	c.-12G>C		splice_region_variant, 5_prime_UTR_variant	2/24
FLT3	NR_130706.2	n.112G>C		splice_region_variant, non_coding_transcript_exon_variant	2/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT3	ENST00000241453.12	c.46G>C	p.Val16Leu	missense_variant, splice_region_variant	2/24	1	NM_004119.3	P1
FLT3	ENST00000380987.2	c.46G>C	p.Val16Leu	missense_variant, splice_region_variant, NMD_transcript_variant	2/25	1

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 340 AN: 152114 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.00144

GnomAD3 exomes AF: 0.000594 AC: 147 AN: 247406 Hom.: 0 AF XY: 0.000515 AC XY: 69 AN XY: 133968

Gnomad AFR exome AF: 0.00814

Gnomad AMR exome AF: 0.000382

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: 0.00000886

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000219 AC: 316 AN: 1444142 Hom.: 1 Cov.: 27 AF XY: 0.000193 AC XY: 139 AN XY: 719536

Gnomad4 AFR exome AF: 0.00859

Gnomad4 AMR exome AF: 0.000361

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: 0.00000182

Gnomad4 OTH exome AF: 0.000234

GnomAD4 genome AF: 0.00224 AC: 341 AN: 152232 Hom.: 3 Cov.: 32 AF XY: 0.00236 AC XY: 176 AN XY: 74448

Gnomad4 AFR AF: 0.00775

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.00250

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000717 AC: 87

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000546

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

Dec 31, 2019

- -

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	0.15
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.91	N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.28
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.39
MVP		0.53
MPC		0.12
ClinPred		0.042	T
GERP RS		1.1
Varity_R		0.064
gMVP		0.29

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: rs62636526; hg19: chr13-28644747;