5-180625108-C-T

Variant names:

• chr5-180625108-C-T
• rs307823
• NM_182925.5:c.1421+761G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182925.5(FLT4):​c.1421+761G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 152,168 control chromosomes in the GnomAD database, including 39,747 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 0.70 (39747 hom., cov: 34)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 10 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.815 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	NM_182925.5	MANE Select	c.1421+761G>A		intron	N/A	NP_891555.2	P35916-2
	FLT4	NM_001354989.2		c.1421+761G>A		intron	N/A	NP_001341918.1	E9PD35
	FLT4	NM_002020.5		c.1421+761G>A		intron	N/A	NP_002011.2	P35916-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	ENST00000261937.11	TSL:1 MANE Select	c.1421+761G>A		intron	N/A	ENSP00000261937.6	P35916-2
	FLT4	ENST00000502649.5	TSL:1	c.1421+761G>A		intron	N/A	ENSP00000426057.1	E9PD35
	FLT4	ENST00000393347.7	TSL:1	c.1421+761G>A		intron	N/A	ENSP00000377016.3	P35916-1

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106818 AN: 152050 Hom.: 39741 Cov.: 34

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.780

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.792

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.821

Gnomad OTH AF: 0.707

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

GnomAD4 genome AF: 0.702 AC: 106847 AN: 152168 Hom.: 39747 Cov.: 34 AF XY: 0.707 AC XY: 52555 AN XY: 74376

African (AFR) AF: 0.452 AC: 18756 AN: 41490

American (AMR) AF: 0.780 AC: 11929 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2451 AN: 3470

East Asian (EAS) AF: 0.491 AC: 2535 AN: 5164

South Asian (SAS) AF: 0.792 AC: 3818 AN: 4822

European-Finnish (FIN) AF: 0.849 AC: 9000 AN: 10600

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.821 AC: 55821 AN: 68014

Other (OTH) AF: 0.700 AC: 1479 AN: 2112

Alfa AF: 0.772 Hom.: 144505

Bravo AF: 0.680

Asia WGS AF: 0.628 AC: 2185 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.55
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs307823; hg19: chr5-180052108;