rs448012

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182925.5(FLT4):c.2670C>G(p.His890Gln) variant causes a missense change. The variant allele was found at a frequency of 0.628 in 1,609,192 control chromosomes in the GnomAD database, including 319,683 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 28934 hom., cov: 32)

Exomes 𝑓: 0.63 ( 290749 hom. )

Consequence

FLT4
NM_182925.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.68

Variant links:

Genes affected

FLT4 (HGNC:3767): (fms related receptor tyrosine kinase 4) This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involved in lymphangiogenesis and maintenance of the lymphatic endothelium. Mutations in this gene cause hereditary lymphedema type IA. [provided by RefSeq, Jul 2008]

FLT4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3976962E-6).

BP6

Variant 5-180619344-G-C is Benign according to our data. Variant chr5-180619344-G-C is described in ClinVar as [Benign]. Clinvar id is 263039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-180619344-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT4	NM_182925.5 linkuse as main transcript	c.2670C>G	p.His890Gln	missense_variant	19/30	ENST00000261937.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT4	ENST00000261937.11 linkuse as main transcript	c.2670C>G	p.His890Gln	missense_variant	19/30	1	NM_182925.5	P1	P35916-2

Frequencies

GnomAD3 genomes

AF:

0.612

AC:

92873

AN:

151658

Hom.:

28920

Cov.:

show subpopulations

Gnomad AFR

AF:

0.543

Gnomad AMI

AF:

0.697

Gnomad AMR

AF:

0.697

Gnomad ASJ

AF:

0.568

Gnomad EAS

AF:

0.494

Gnomad SAS

AF:

0.578

Gnomad FIN

AF:

0.704

Gnomad MID

AF:

0.600

Gnomad NFE

AF:

0.634

Gnomad OTH

AF:

0.624

GnomAD3 exomes

AF:

0.630

AC:

153516

AN:

243662

Hom.:

49194

AF XY:

0.623

AC XY:

82868

AN XY:

133036

show subpopulations

Gnomad AFR exome

AF:

0.543

Gnomad AMR exome

AF:

0.755

Gnomad ASJ exome

AF:

0.571

Gnomad EAS exome

AF:

0.488

Gnomad SAS exome

AF:

0.567

Gnomad FIN exome

AF:

0.704

Gnomad NFE exome

AF:

0.636

Gnomad OTH exome

AF:

0.628

GnomAD4 exome

AF:

0.630

AC:

917892

AN:

1457416

Hom.:

290749

Cov.:

AF XY:

0.627

AC XY:

455002

AN XY:

725184

show subpopulations

Gnomad4 AFR exome

AF:

0.537

Gnomad4 AMR exome

AF:

0.749

Gnomad4 ASJ exome

AF:

0.580

Gnomad4 EAS exome

AF:

0.494

Gnomad4 SAS exome

AF:

0.569

Gnomad4 FIN exome

AF:

0.705

Gnomad4 NFE exome

AF:

0.636

Gnomad4 OTH exome

AF:

0.617

GnomAD4 genome

AF:

0.612

AC:

92924

AN:

151776

Hom.:

28934

Cov.:

AF XY:

0.616

AC XY:

45667

AN XY:

74170

show subpopulations

Gnomad4 AFR

AF:

0.542

Gnomad4 AMR

AF:

0.697

Gnomad4 ASJ

AF:

0.568

Gnomad4 EAS

AF:

0.493

Gnomad4 SAS

AF:

0.578

Gnomad4 FIN

AF:

0.704

Gnomad4 NFE

AF:

0.634

Gnomad4 OTH

AF:

0.619

Alfa

AF:

0.625

Hom.:

9730

Bravo

AF:

0.608

TwinsUK

AF:

0.646

AC:

2394

ALSPAC

AF:

0.643

AC:

2479

ESP6500AA

AF:

0.545

AC:

2398

ESP6500EA

AF:

0.623

AC:

5356

ExAC

AF:

0.621

AC:

74755

Asia WGS

AF:

0.544

AC:

1889

AN:

3478

EpiCase

AF:

0.627

EpiControl

AF:

0.624

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 62% of total chromosomes in ExAC -

Congenital heart defects, multiple types, 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Hereditary lymphedema type I

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.61

D;.;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.75

T;T;T

MetaRNN

Benign

0.0000014

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.040

N;N;.

MutationTaster

Benign

0.000013

P;P;P

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.1

D;D;D

REVEL

Uncertain

0.31

Sift

Benign

0.045

D;D;D

Sift4G

Uncertain

0.033

D;D;D

Polyphen

0.18

B;.;B

Vest4

0.39

MutPred

0.19

Gain of catalytic residue at H890 (P = 0.0859);Gain of catalytic residue at H890 (P = 0.0859);Gain of catalytic residue at H890 (P = 0.0859);

MPC

1.2

ClinPred

0.050

GERP RS

1.2

Varity_R

0.50

gMVP

0.77

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over