Genetic Variant NM_182925.5:c.3894-2495T>C (chr5-180605885-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_182925.5(FLT4):c.3894-2495T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 152,066 control chromosomes in the GnomAD database, including 11,959 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.38 ( 11959 hom., cov: 33)

Consequence

FLT4
NM_182925.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.292

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

lymphatic malformation 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
capillary infantile hemangioma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
congenital heart defects, multiple types, 7
Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
lymphatic malformation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
tetralogy of fallot
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FLT4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5 link	c.3894-2495T>C		intron_variant	Intron 29 of 29	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.3894-2495T>C		intron_variant	Intron 29 of 29	1	NM_182925.5	ENSP00000261937.6		P35916-2
FLT4	ENST00000502603.5 link	n.594-2495T>C		intron_variant	Intron 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.385

AC:

58473

AN:

151948

Hom.:

11943

Cov.:

show subpopulations

Gnomad AFR

AF:

0.513

Gnomad AMI

AF:

0.214

Gnomad AMR

AF:

0.302

Gnomad ASJ

AF:

0.418

Gnomad EAS

AF:

0.577

Gnomad SAS

AF:

0.392

Gnomad FIN

AF:

0.282

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.327

Gnomad OTH

AF:

0.380

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.385

AC:

58529

AN:

152066

Hom.:

11959

Cov.:

AF XY:

0.383

AC XY:

28497

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.513

AC:

21268

AN:

41488

American (AMR)

AF:

0.302

AC:

4607

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.418

AC:

1450

AN:

3470

East Asian (EAS)

AF:

0.578

AC:

2977

AN:

5152

South Asian (SAS)

AF:

0.391

AC:

1885

AN:

4822

European-Finnish (FIN)

AF:

0.282

AC:

2985

AN:

10590

Middle Eastern (MID)

AF:

0.432

AC:

127

AN:

294

European-Non Finnish (NFE)

AF:

0.327

AC:

22221

AN:

67954

Other (OTH)

AF:

0.386

AC:

814

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1834

3669

5503

7338

9172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

570

1140

1710

2280

2850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.352

Hom.:

2005

Bravo

AF:

0.395

Asia WGS

AF:

0.480

AC:

1672

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.1

(source)

DANN

Benign

0.38

PhyloP100

-0.29

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over