Genetic Variant FLT4:p.Asn149Asp (chr5-180630293-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_182925.5(FLT4):c.445A>G(p.Asn149Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.092 in 1,612,212 control chromosomes in the GnomAD database, including 7,695 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.070 ( 525 hom., cov: 32)

Exomes 𝑓: 0.094 ( 7170 hom. )

Consequence

FLT4
NM_182925.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.40

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=0.0018151104).

BP6

Variant 5-180630293-T-C is Benign according to our data. Variant chr5-180630293-T-C is described in ClinVar as [Benign]. Clinvar id is 263062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-180630293-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5 link	c.445A>G	p.Asn149Asp	missense_variant	Exon 4 of 30	ENST00000261937.11	NP_891555.2	P35916-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLT4	ENST00000261937.11 link	c.445A>G	p.Asn149Asp	missense_variant	Exon 4 of 30	1	NM_182925.5	ENSP00000261937.6		P35916-2

Frequencies

GnomAD3 genomes

AF:

0.0704

AC:

10715

AN:

152134

Hom.:

525

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0191

Gnomad AMI

AF:

0.150

Gnomad AMR

AF:

0.0500

Gnomad ASJ

AF:

0.0625

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0414

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.0699

GnomAD3 exomes

AF:

0.0738

AC:

18397

AN:

249392

Hom.:

910

AF XY:

0.0745

AC XY:

10087

AN XY:

135438

show subpopulations

Gnomad AFR exome

AF:

0.0174

Gnomad AMR exome

AF:

0.0373

Gnomad ASJ exome

AF:

0.0673

Gnomad EAS exome

AF:

0.000490

Gnomad SAS exome

AF:

0.0453

Gnomad FIN exome

AF:

0.116

Gnomad NFE exome

AF:

0.105

Gnomad OTH exome

AF:

0.0751

GnomAD4 exome

AF:

0.0943

AC:

137692

AN:

1459960

Hom.:

7170

Cov.:

AF XY:

0.0928

AC XY:

67414

AN XY:

726352

show subpopulations

Gnomad4 AFR exome

AF:

0.0152

Gnomad4 AMR exome

AF:

0.0390

Gnomad4 ASJ exome

AF:

0.0665

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0466

Gnomad4 FIN exome

AF:

0.119

Gnomad4 NFE exome

AF:

0.106

Gnomad4 OTH exome

AF:

0.0813

GnomAD4 genome

AF:

0.0704

AC:

10712

AN:

152252

Hom.:

525

Cov.:

AF XY:

0.0683

AC XY:

5087

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0190

Gnomad4 AMR

AF:

0.0498

Gnomad4 ASJ

AF:

0.0625

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0417

Gnomad4 FIN

AF:

0.118

Gnomad4 NFE

AF:

0.106

Gnomad4 OTH

AF:

0.0687

Alfa

AF:

0.0902

Hom.:

427

Bravo

AF:

0.0632

TwinsUK

AF:

0.104

AC:

385

ALSPAC

AF:

0.108

AC:

415

ESP6500AA

AF:

0.0218

AC:

ESP6500EA

AF:

0.0975

AC:

838

ExAC

AF:

0.0747

AC:

9037

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0937

EpiControl

AF:

0.101

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

T;.;T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.63

T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.0

N;N;N;.

REVEL

Benign

0.064

Sift

Benign

0.19

T;T;T;.

Sift4G

Benign

0.21

T;T;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.061

MPC

0.68

ClinPred

0.0043

GERP RS

3.0

Varity_R

0.14

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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