5-180630231-C-A

Variant names:

• chr5-180630231-C-A
• rs3736061
• NM_182925.5:c.507G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182925.5(FLT4):​c.507G>T​(p.Leu169Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0791 in 1,612,042 control chromosomes in the GnomAD database, including 5,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (475 hom., cov: 32)
  • Exomes 𝑓: 0.080 (5184 hom.)
• Consequence: FLT4 NM_182925.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.144
• Publications: 22 publications found

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 Gene-Disease associations (from GenCC):

• congenital heart defects, multiple types, 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• lymphatic malformation 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• capillary infantile hemangioma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• lymphatic malformation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tetralogy of fallot

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 5-180630231-C-A is Benign according to our data. Variant chr5-180630231-C-A is described in ClinVar as Benign. ClinVar VariationId is 263064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.144 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182925.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	NM_182925.5	MANE Select	c.507G>T	p.Leu169Leu	synonymous	Exon 4 of 30	NP_891555.2	P35916-2
	FLT4	NM_001354989.2		c.507G>T	p.Leu169Leu	synonymous	Exon 4 of 30	NP_001341918.1	E9PD35
	FLT4	NM_002020.5		c.507G>T	p.Leu169Leu	synonymous	Exon 4 of 30	NP_002011.2	P35916-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	ENST00000261937.11	TSL:1 MANE Select	c.507G>T	p.Leu169Leu	synonymous	Exon 4 of 30	ENSP00000261937.6	P35916-2
	FLT4	ENST00000502649.5	TSL:1	c.507G>T	p.Leu169Leu	synonymous	Exon 4 of 30	ENSP00000426057.1	E9PD35
	FLT4	ENST00000393347.7	TSL:1	c.507G>T	p.Leu169Leu	synonymous	Exon 4 of 30	ENSP00000377016.3	P35916-1

Frequencies

GnomAD3 genomes AF: 0.0670 AC: 10183 AN: 152082 Hom.: 475 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0465

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0590

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0867

Gnomad OTH AF: 0.0535

GnomAD2 exomes AF: 0.0766 AC: 19113 AN: 249510 AF XY: 0.0775

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.0313

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.117

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.0800

Gnomad OTH exome AF: 0.0760

GnomAD4 exome AF: 0.0803 AC: 117259 AN: 1459842 Hom.: 5184 Cov.: 35 AF XY: 0.0804 AC XY: 58379 AN XY: 726238

African (AFR) AF: 0.0119 AC: 399 AN: 33472

American (AMR) AF: 0.0340 AC: 1520 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 3538 AN: 26120

East Asian (EAS) AF: 0.128 AC: 5079 AN: 39688

South Asian (SAS) AF: 0.0628 AC: 5414 AN: 86248

European-Finnish (FIN) AF: 0.125 AC: 6482 AN: 51978

Middle Eastern (MID) AF: 0.0392 AC: 226 AN: 5768

European-Non Finnish (NFE) AF: 0.0808 AC: 89849 AN: 1111492

Other (OTH) AF: 0.0787 AC: 4752 AN: 60358

GnomAD4 genome AF: 0.0669 AC: 10182 AN: 152200 Hom.: 475 Cov.: 32 AF XY: 0.0679 AC XY: 5052 AN XY: 74408

African (AFR) AF: 0.0139 AC: 579 AN: 41554

American (AMR) AF: 0.0464 AC: 710 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3470

East Asian (EAS) AF: 0.119 AC: 616 AN: 5156

South Asian (SAS) AF: 0.0594 AC: 287 AN: 4828

European-Finnish (FIN) AF: 0.139 AC: 1473 AN: 10580

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0866 AC: 5892 AN: 67998

Other (OTH) AF: 0.0553 AC: 117 AN: 2114

Alfa AF: 0.0756 Hom.: 982

Bravo AF: 0.0562

Asia WGS AF: 0.0920 AC: 322 AN: 3478

EpiCase AF: 0.0778

EpiControl AF: 0.0746

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.3
DANN	Benign	0.55
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3736061; hg19: chr5-180057231; COSMIC: COSV56099321; COSMIC: COSV56099321;