rs1130378

chr5-180616388-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182925.5(FLT4):c.3198C>T(p.Pro1066=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,613,624 control chromosomes in the GnomAD database, including 62,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4913 hom., cov: 32)
  • Exomes 𝑓: 0.28 (57192 hom.)
• Consequence: FLT4 NM_182925.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.889

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 5-180616388-G-A is Benign according to our data. Variant chr5-180616388-G-A is described in ClinVar as [Benign]. Clinvar id is 263044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-180616388-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.889 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT4	NM_182925.5	c.3198C>T	p.Pro1066=	synonymous_variant	23/30	ENST00000261937.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT4	ENST00000261937.11	c.3198C>T	p.Pro1066=	synonymous_variant	23/30	1	NM_182925.5	P1

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37313 AN: 152096 Hom.: 4917 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.262

GnomAD3 exomes AF: 0.265 AC: 66588 AN: 251220 Hom.: 9391 AF XY: 0.277 AC XY: 37594 AN XY: 135868

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.316

Gnomad EAS exome AF: 0.248

Gnomad SAS exome AF: 0.352

Gnomad FIN exome AF: 0.227

Gnomad NFE exome AF: 0.287

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.277 AC: 405478 AN: 1461408 Hom.: 57192 Cov.: 40 AF XY: 0.281 AC XY: 204249 AN XY: 727018

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.313

Gnomad4 EAS exome AF: 0.249

Gnomad4 SAS exome AF: 0.347

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.281

Gnomad4 OTH exome AF: 0.281

GnomAD4 genome AF: 0.245 AC: 37310 AN: 152216 Hom.: 4913 Cov.: 32 AF XY: 0.245 AC XY: 18254 AN XY: 74424

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.219

Gnomad4 ASJ AF: 0.322

Gnomad4 EAS AF: 0.255

Gnomad4 SAS AF: 0.332

Gnomad4 FIN AF: 0.229

Gnomad4 NFE AF: 0.288

Gnomad4 OTH AF: 0.259

Alfa AF: 0.270 Hom.: 4007

Bravo AF: 0.238

Asia WGS AF: 0.258 AC: 898 AN: 3478

EpiCase AF: 0.295

EpiControl AF: 0.295

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Congenital heart defects, multiple types, 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Hereditary lymphedema type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	3.6
Dann	Benign	0.74

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: rs1130378; hg19: chr5-180043388; COSMIC: COSV56099249; COSMIC: COSV56099249;