5-180603313-C-G

Position:

• chr5-180603313-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182925.5(FLT4):​c.3971G>C​(p.Arg1324Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000959 in 1,613,776 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1324L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00098 (5 hom.)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.34

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005812019).
• BP6: Variant 5-180603313-C-G is Benign according to our data. Variant chr5-180603313-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 263056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-180603313-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000728 (111/152378) while in subpopulation NFE AF= 0.0011 (75/68038). AF 95% confidence interval is 0.000901. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLT4	NM_182925.5	c.3971G>C	p.Arg1324Pro	missense_variant	30/30	ENST00000261937.11	NP_891555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLT4	ENST00000261937.11	c.3971G>C	p.Arg1324Pro	missense_variant	30/30	1	NM_182925.5	ENSP00000261937.6
FLT4	ENST00000502603.5	n.671G>C		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000741 AC: 183 AN: 246898 Hom.: 0 AF XY: 0.000784 AC XY: 105 AN XY: 133964

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.000800

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000983 AC: 1437 AN: 1461398 Hom.: 5 Cov.: 32 AF XY: 0.00103 AC XY: 752 AN XY: 726960

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.000613

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.000746

GnomAD4 genome AF: 0.000728 AC: 111 AN: 152378 Hom.: 0 Cov.: 33 AF XY: 0.000711 AC XY: 53 AN XY: 74524

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000129 Hom.: 158

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000733 AC: 89

EpiCase AF: 0.00115

EpiControl AF: 0.00143

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	FLT4: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.017
DANN	Benign	0.80
DEOGEN2	Benign	0.077	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.76	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.087
Sift	Benign	0.21	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.055
MVP		0.068
MPC		0.17
ClinPred		0.0047	T
GERP RS		-8.8
Varity_R		0.061
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs307821; hg19: chr5-180030313; COSMIC: COSV56098908; COSMIC: COSV56098908;