Genetic Variant NM_182925.5:c.677-28G>A (chr5-180629863-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182925.5(FLT4):c.677-28G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0359 in 1,612,426 control chromosomes in the GnomAD database, including 1,161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 151 hom., cov: 33)

Exomes 𝑓: 0.035 ( 1010 hom. )

Consequence

FLT4
NM_182925.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.00

Publications

4 publications found

Variant links:

COSMIC-nc: COSV56108162

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):

congenital heart defects, multiple types, 7
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
lymphatic malformation 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
capillary infantile hemangioma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 5-180629863-C-T is Benign according to our data. Variant chr5-180629863-C-T is described in ClinVar as Benign. ClinVar VariationId is 263070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182925.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FLT4	NM_182925.5	MANE Select	c.677-28G>A	intron	N/A	NP_891555.2	P35916-2
FLT4	NM_001354989.2		c.677-28G>A	intron	N/A	NP_001341918.1	E9PD35
FLT4	NM_002020.5		c.677-28G>A	intron	N/A	NP_002011.2	P35916-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FLT4	ENST00000261937.11	TSL:1 MANE Select	c.677-28G>A	intron	N/A	ENSP00000261937.6	P35916-2
FLT4	ENST00000502649.5	TSL:1	c.677-28G>A	intron	N/A	ENSP00000426057.1	E9PD35
FLT4	ENST00000393347.7	TSL:1	c.677-28G>A	intron	N/A	ENSP00000377016.3	P35916-1

Frequencies

GnomAD3 genomes

AF:

0.0422

AC:

6416

AN:

152190

Hom.:

150

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0651

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.0298

Gnomad ASJ

AF:

0.0259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0199

Gnomad FIN

AF:

0.0397

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0368

Gnomad OTH

AF:

0.0325

GnomAD2 exomes

AF:

0.0313

AC:

7783

AN:

248412

AF XY:

0.0313

show subpopulations

Gnomad AFR exome

AF:

0.0675

Gnomad AMR exome

AF:

0.0165

Gnomad ASJ exome

AF:

0.0303

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0362

Gnomad NFE exome

AF:

0.0374

Gnomad OTH exome

AF:

0.0378

GnomAD4 exome

AF:

0.0352

AC:

51415

AN:

1460118

Hom.:

1010

Cov.:

AF XY:

0.0348

AC XY:

25256

AN XY:

726284

show subpopulations

African (AFR)

AF:

0.0682

AC:

2281

AN:

33458

American (AMR)

AF:

0.0183

AC:

819

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0294

AC:

769

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39682

South Asian (SAS)

AF:

0.0208

AC:

1788

AN:

86168

European-Finnish (FIN)

AF:

0.0369

AC:

1922

AN:

52130

Middle Eastern (MID)

AF:

0.0652

AC:

376

AN:

5768

European-Non Finnish (NFE)

AF:

0.0371

AC:

41192

AN:

1111748

Other (OTH)

AF:

0.0375

AC:

2266

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

3117

6234

9350

12467

15584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1546

3092

4638

6184

7730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0422

AC:

6427

AN:

152308

Hom.:

151

Cov.:

AF XY:

0.0424

AC XY:

3157

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0651

AC:

2708

AN:

41568

American (AMR)

AF:

0.0298

AC:

456

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0199

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0397

AC:

422

AN:

10618

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0368

AC:

2506

AN:

68022

Other (OTH)

AF:

0.0317

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

340

680

1020

1360

1700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<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:

0.0344

Hom.:

137

Bravo

AF:

0.0427

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.032

(source)

DANN

Benign

0.71

PhyloP100

-2.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over