rs1130379

Variant names:

• chr5-180612606-C-A
• rs1130379
• NM_182925.5:c.3437G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-180612606-C-A
• chr5-180612606-C-G
• chr5-180612606-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_182925.5(FLT4):​c.3437G>T​(p.Arg1146Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,544 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1146H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.746
• Publications: 0 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):

• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3437G>T	p.Arg1146Leu	missense	Exon 26 of 30	NP_891555.2
	FLT4	NM_001354989.2		c.3437G>T	p.Arg1146Leu	missense	Exon 26 of 30	NP_001341918.1
	FLT4	NM_002020.5		c.3437G>T	p.Arg1146Leu	missense	Exon 26 of 30	NP_002011.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	ENST00000261937.11	TSL:1 MANE Select	c.3437G>T	p.Arg1146Leu	missense	Exon 26 of 30	ENSP00000261937.6
	FLT4	ENST00000502649.5	TSL:1	c.3437G>T	p.Arg1146Leu	missense	Exon 26 of 30	ENSP00000426057.1
	FLT4	ENST00000393347.7	TSL:1	c.3437G>T	p.Arg1146Leu	missense	Exon 26 of 30	ENSP00000377016.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460544 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726710

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110824

Other (OTH) AF: 0.0000166 AC: 1 AN: 60348

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	9.1
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.81
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.75
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.013	D
Sift4G	Benign	0.062	T
Polyphen		0.20	B
Vest4		0.58
MutPred		0.61		Loss of MoRF binding (P = 0.0092)
MVP		0.50
MPC		1.1
ClinPred		0.32	T
GERP RS		-0.63
Varity_R		0.23
gMVP		0.49
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1130379; hg19: chr5-180039606;