5-180603376-C-G

Position:

• chr5-180603376-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.3908G>C​(p.Gly1303Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,613,944 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (21 hom.)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.35

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=0.0036003888).
• BP6: Variant 5-180603376-C-G is Benign according to our data. Variant chr5-180603376-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 263053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-180603376-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00259 (394/152354) while in subpopulation SAS AF= 0.0089 (43/4834). AF 95% confidence interval is 0.00679. There are 1 homozygotes in gnomad4. There are 204 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLT4	NM_182925.5	c.3908G>C	p.Gly1303Ala	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.3908G>C	p.Gly1303Ala	missense_variant	30/30	1	NM_182925.5	ENSP00000261937.6
FLT4	ENST00000502603.5	n.608G>C		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00257 AC: 392 AN: 152236 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00847

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00340

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00323 AC: 801 AN: 247888 Hom.: 4 AF XY: 0.00364 AC XY: 489 AN XY: 134328

Gnomad AFR exome AF: 0.000373

Gnomad AMR exome AF: 0.00232

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0100

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.00343

Gnomad OTH exome AF: 0.00361

GnomAD4 exome AF: 0.00306 AC: 4473 AN: 1461590 Hom.: 21 Cov.: 32 AF XY: 0.00330 AC XY: 2400 AN XY: 727066

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.000498

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00283

Gnomad4 OTH exome AF: 0.00358

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152354 Hom.: 1 Cov.: 33 AF XY: 0.00274 AC XY: 204 AN XY: 74490

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00890

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00340

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00249 Hom.: 0

Bravo AF: 0.00280

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00334 AC: 405

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00416

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 08, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	FLT4: BP4, BS1, BS2 -

not specified Benign:1

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	0.075
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.17
Sift	Benign	0.46	T
Sift4G	Benign	0.54	T
Polyphen		0.0020	B
Vest4		0.14
MVP		0.33
MPC		0.13
ClinPred		0.0033	T
GERP RS		0.47
Varity_R		0.049
gMVP		0.11

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: rs146806202; hg19: chr5-180030376; COSMIC: COSV56118431; COSMIC: COSV56118431;