chr5-180619743-C-T

Variant names:

• chr5-180619743-C-T
• rs267606818
• NM_182925.5:c.2569G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS1 PM2 PP3_Strong PP5_Very_Strong

The NM_182925.5(FLT4):​c.2569G>A​(p.Gly857Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.90
• Publications: 11 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: Pathogenic. The variant received 18 ACMG points.

• PS1: Transcript NM_182925.5 (FLT4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 5-180619743-C-T is Pathogenic according to our data. Variant chr5-180619743-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2569G>A	p.Gly857Arg	missense	Exon 18 of 30	NP_891555.2
	FLT4	NM_001354989.2		c.2569G>A	p.Gly857Arg	missense	Exon 18 of 30	NP_001341918.1
	FLT4	NM_002020.5		c.2569G>A	p.Gly857Arg	missense	Exon 18 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.2569G>A	p.Gly857Arg	missense	Exon 18 of 30	ENSP00000261937.6
	FLT4	ENST00000502649.5	TSL:1	c.2569G>A	p.Gly857Arg	missense	Exon 18 of 30	ENSP00000426057.1
	FLT4	ENST00000393347.7	TSL:1	c.2569G>A	p.Gly857Arg	missense	Exon 18 of 30	ENSP00000377016.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary lymphedema type I (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.99		Gain of MoRF binding (P = 0.0084)
MVP		0.97
MPC		1.7
ClinPred		1.0	D
GERP RS		4.3
PromoterAI		0.021	Neutral
Varity_R		0.89
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267606818; hg19: chr5-180046743;