rs34255532

chr5-180618911-G-Achr5-180618911-G-C

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.2860C>T(p.Pro954Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0057 in 1,585,876 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (32 hom.)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:7
• Conservation: PhyloP100: 3.79

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006272793).
• BP6: Variant 5-180618911-G-A is Benign according to our data. Variant chr5-180618911-G-A is described in ClinVar as [Benign]. Clinvar id is 16264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-180618911-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00346 (527/152298) while in subpopulation NFE AF= 0.00619 (421/68010). AF 95% confidence interval is 0.0057. There are 4 homozygotes in gnomad4. There are 225 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT4	NM_182925.5	c.2860C>T	p.Pro954Ser	missense_variant	21/30	ENST00000261937.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT4	ENST00000261937.11	c.2860C>T	p.Pro954Ser	missense_variant	21/30	1	NM_182925.5	P1

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 527 AN: 152182 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00619

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00354 AC: 681 AN: 192522 Hom.: 4 AF XY: 0.00372 AC XY: 393 AN XY: 105698

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.000228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00410

Gnomad FIN exome AF: 0.000472

Gnomad NFE exome AF: 0.00600

Gnomad OTH exome AF: 0.00422

GnomAD4 exome AF: 0.00594 AC: 8519 AN: 1433578 Hom.: 32 Cov.: 34 AF XY: 0.00597 AC XY: 4242 AN XY: 710598

Gnomad4 AFR exome AF: 0.00115

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.000157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00368

Gnomad4 FIN exome AF: 0.000632

Gnomad4 NFE exome AF: 0.00699

Gnomad4 OTH exome AF: 0.00618

GnomAD4 genome AF: 0.00346 AC: 527 AN: 152298 Hom.: 4 Cov.: 33 AF XY: 0.00302 AC XY: 225 AN XY: 74468

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00619

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00493 Hom.: 7

Bravo AF: 0.00354

ESP6500AA AF: 0.00163 AC: 7

ESP6500EA AF: 0.00496 AC: 42

ExAC AF: 0.00307 AC: 362

Asia WGS AF: 0.00115 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	FLT4: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Capillary infantile hemangioma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2002

- -

Colorectal cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.40	T;.;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.69	T;T;T
MetaRNN	Benign	0.0063	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.80	N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.088	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.016	B;.;B
Vest4		0.23
MVP		0.41
MPC		0.78
ClinPred		0.011	T
GERP RS		4.0
Varity_R		0.15
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs34255532; hg19: chr5-180045911; COSMIC: COSV56128641; COSMIC: COSV56128641;