5-180603221-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_182925.5(FLT4):c.4063G>A(p.Val1355Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000899 in 1,614,070 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00083 (4 hom.)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.53

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066666305).
• BP6: Variant 5-180603221-C-T is Benign according to our data. Variant chr5-180603221-C-T is described in ClinVar as [Benign]. Clinvar id is 3042470.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-180603221-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00158 (240/152370) while in subpopulation AFR AF= 0.00358 (149/41592). AF 95% confidence interval is 0.00311. There are 0 homozygotes in gnomad4. There are 115 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT4	NM_182925.5	c.4063G>A	p.Val1355Met	missense_variant	30/30	ENST00000261937.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT4	ENST00000261937.11	c.4063G>A	p.Val1355Met	missense_variant	30/30	1	NM_182925.5	P1
FLT4	ENST00000502603.5	n.763G>A		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 240 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00137 AC: 343 AN: 249466 Hom.: 0 AF XY: 0.00120 AC XY: 162 AN XY: 135256

Gnomad AFR exome AF: 0.00399

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00889

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000961

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.000828 AC: 1211 AN: 1461700 Hom.: 4 Cov.: 31 AF XY: 0.000802 AC XY: 583 AN XY: 727170

Gnomad4 AFR exome AF: 0.00394

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.00849

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.000492

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152370 Hom.: 0 Cov.: 33 AF XY: 0.00154 AC XY: 115 AN XY: 74514

Gnomad4 AFR AF: 0.00358

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00128 Hom.: 1

Bravo AF: 0.00181

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00128 AC: 155

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00136

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

FLT4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	3.7
Dann	Benign	0.96
DEOGEN2	Benign	0.079	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.27
Sift	Benign	0.055	T
Sift4G	Uncertain	0.046	D
Polyphen		0.85	P
Vest4		0.089
MVP		0.24
MPC		0.19
ClinPred		0.012	T
GERP RS		-4.7
Varity_R		0.022
gMVP		0.21

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: rs143739828; hg19: chr5-180030221; COSMIC: COSV56097856; COSMIC: COSV56097856;