NM_004119.3:c.580G>A

Variant names:

• chr13-28052579-C-T
• rs146030737
• NM_004119.3:c.580G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004119.3(FLT3):​c.580G>A​(p.Val194Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00469 in 1,613,596 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (26 hom.)
• Consequence: FLT3 NM_004119.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.01
• Publications: 31 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00608474).
• BP6: Variant 13-28052579-C-T is Benign according to our data. Variant chr13-28052579-C-T is described in ClinVar as Benign. ClinVar VariationId is 134446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00424 (646/152300) while in subpopulation NFE AF = 0.00582 (396/68028). AF 95% confidence interval is 0.00535. There are 4 homozygotes in GnomAd4. There are 319 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 646 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT3	NM_004119.3	MANE Select	c.580G>A	p.Val194Met	missense	Exon 5 of 24	NP_004110.2
	FLT3	NR_130706.2		n.646G>A		non_coding_transcript_exon	Exon 5 of 25

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT3	ENST00000241453.12	TSL:1 MANE Select	c.580G>A	p.Val194Met	missense	Exon 5 of 24	ENSP00000241453.7
	FLT3	ENST00000380987.2	TSL:1	n.580G>A		non_coding_transcript_exon	Exon 5 of 25	ENSP00000370374.2

Frequencies

GnomAD3 genomes AF: 0.00424 AC: 646 AN: 152182 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00582

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00501 AC: 1259 AN: 251274 AF XY: 0.00522

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00290

Gnomad ASJ exome AF: 0.0261

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00453

Gnomad NFE exome AF: 0.00609

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00474 AC: 6921 AN: 1461296 Hom.: 26 Cov.: 30 AF XY: 0.00482 AC XY: 3507 AN XY: 726964

African (AFR) AF: 0.000568 AC: 19 AN: 33464

American (AMR) AF: 0.00269 AC: 120 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 618 AN: 26118

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39692

South Asian (SAS) AF: 0.00190 AC: 164 AN: 86200

European-Finnish (FIN) AF: 0.00427 AC: 228 AN: 53400

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.00488 AC: 5421 AN: 1111640

Other (OTH) AF: 0.00515 AC: 311 AN: 60364

GnomAD4 genome AF: 0.00424 AC: 646 AN: 152300 Hom.: 4 Cov.: 32 AF XY: 0.00428 AC XY: 319 AN XY: 74468

African (AFR) AF: 0.000626 AC: 26 AN: 41556

American (AMR) AF: 0.00405 AC: 62 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.00480 AC: 51 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00582 AC: 396 AN: 68028

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00619 Hom.: 5

Bravo AF: 0.00400

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.00516 AC: 626

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00557

EpiControl AF: 0.00694

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.014
Eigen_PC	Benign	0.026
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.0
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.22
Sift	Benign	0.072	T
Sift4G	Benign	0.11	T
Polyphen		0.95	P
Vest4		0.27
MVP		0.64
MPC		0.17
ClinPred		0.0065	T
GERP RS		3.6
Varity_R		0.087
gMVP		0.58
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs146030737; hg19: chr13-28626716; COSMIC: COSV54058930;