chr5-180630249-G-A

Variant names:

• chr5-180630249-G-A
• rs75516704
• NM_182925.5:c.489C>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.489C>T​(p.Pro163Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00678 in 1,612,428 control chromosomes in the GnomAD database, including 405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (186 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (219 hom.)
• Consequence: FLT4 NM_182925.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.39
• Publications: 2 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):

• lymphatic malformation 1

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

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• congenital heart defects, multiple types, 7

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.9).
• BP6: Variant 5-180630249-G-A is Benign according to our data. Variant chr5-180630249-G-A is described in ClinVar as Benign. ClinVar VariationId is 263063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0856 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	NM_182925.5	MANE Select	c.489C>T	p.Pro163Pro	synonymous	Exon 4 of 30	NP_891555.2
	FLT4	NM_001354989.2		c.489C>T	p.Pro163Pro	synonymous	Exon 4 of 30	NP_001341918.1
	FLT4	NM_002020.5		c.489C>T	p.Pro163Pro	synonymous	Exon 4 of 30	NP_002011.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	ENST00000261937.11	TSL:1 MANE Select	c.489C>T	p.Pro163Pro	synonymous	Exon 4 of 30	ENSP00000261937.6
	FLT4	ENST00000502649.5	TSL:1	c.489C>T	p.Pro163Pro	synonymous	Exon 4 of 30	ENSP00000426057.1
	FLT4	ENST00000393347.7	TSL:1	c.489C>T	p.Pro163Pro	synonymous	Exon 4 of 30	ENSP00000377016.3

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4127 AN: 152142 Hom.: 185 Cov.: 32

Gnomad AFR AF: 0.0880

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0310

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.0108 AC: 2694 AN: 249674 AF XY: 0.00999

Gnomad AFR exome AF: 0.0940

Gnomad AMR exome AF: 0.00527

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000453

Gnomad OTH exome AF: 0.00541

GnomAD4 exome AF: 0.00466 AC: 6798 AN: 1460168 Hom.: 219 Cov.: 35 AF XY: 0.00507 AC XY: 3684 AN XY: 726386

African (AFR) AF: 0.0929 AC: 3109 AN: 33478

American (AMR) AF: 0.00573 AC: 256 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.0299 AC: 2579 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51988

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.000273 AC: 304 AN: 1111790

Other (OTH) AF: 0.00850 AC: 513 AN: 60364

GnomAD4 genome AF: 0.0272 AC: 4138 AN: 152260 Hom.: 186 Cov.: 32 AF XY: 0.0265 AC XY: 1974 AN XY: 74438

African (AFR) AF: 0.0880 AC: 3654 AN: 41540

American (AMR) AF: 0.0164 AC: 251 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0309 AC: 149 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68008

Other (OTH) AF: 0.0246 AC: 52 AN: 2110

Alfa AF: 0.0262 Hom.: 93

Bravo AF: 0.0310

Asia WGS AF: 0.0200 AC: 68 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.029
DANN	Benign	0.71
PhyloP100		-5.4
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs75516704; hg19: chr5-180057249; COSMIC: COSV107246725; COSMIC: COSV107246725;