rs2242217

Variant names:

• chr5-180613918-G-A
• rs2242217
• NM_182925.5:c.3331+150C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_182925.5(FLT4):​c.3331+150C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 705,214 control chromosomes in the GnomAD database, including 71,017 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (13236 hom., cov: 33)
  • Exomes 𝑓: 0.45 (57781 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0770
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 5-180613918-G-A is Benign according to our data. Variant chr5-180613918-G-A is described in ClinVar as Benign. ClinVar VariationId is 1260711.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.472 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.3331+150C>T		intron	N/A	NP_891555.2
	FLT4	NM_001354989.2		c.3331+150C>T		intron	N/A	NP_001341918.1
	FLT4	NM_002020.5		c.3331+150C>T		intron	N/A	NP_002011.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	ENST00000261937.11	TSL:1 MANE Select	c.3331+150C>T		intron	N/A	ENSP00000261937.6
	FLT4	ENST00000502649.5	TSL:1	c.3331+150C>T		intron	N/A	ENSP00000426057.1
	FLT4	ENST00000393347.7	TSL:1	c.3331+150C>T		intron	N/A	ENSP00000377016.3

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61622 AN: 151918 Hom.: 13241 Cov.: 33

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.417

GnomAD4 exome AF: 0.452 AC: 249858 AN: 553178 Hom.: 57781 Cov.: 5 AF XY: 0.453 AC XY: 135308 AN XY: 298572

African (AFR) AF: 0.252 AC: 3976 AN: 15786

American (AMR) AF: 0.416 AC: 14387 AN: 34600

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 8136 AN: 19766

East Asian (EAS) AF: 0.290 AC: 9248 AN: 31906

South Asian (SAS) AF: 0.458 AC: 28668 AN: 62592

European-Finnish (FIN) AF: 0.514 AC: 18865 AN: 36700

Middle Eastern (MID) AF: 0.435 AC: 1635 AN: 3756

European-Non Finnish (NFE) AF: 0.476 AC: 151285 AN: 317672

Other (OTH) AF: 0.449 AC: 13658 AN: 30400

GnomAD4 genome AF: 0.405 AC: 61627 AN: 152036 Hom.: 13236 Cov.: 33 AF XY: 0.408 AC XY: 30336 AN XY: 74322

African (AFR) AF: 0.257 AC: 10653 AN: 41444

American (AMR) AF: 0.434 AC: 6639 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1347 AN: 3470

East Asian (EAS) AF: 0.308 AC: 1588 AN: 5160

South Asian (SAS) AF: 0.471 AC: 2268 AN: 4818

European-Finnish (FIN) AF: 0.511 AC: 5405 AN: 10586

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.476 AC: 32363 AN: 67958

Other (OTH) AF: 0.413 AC: 873 AN: 2116

Alfa AF: 0.459 Hom.: 32591

Bravo AF: 0.391

Asia WGS AF: 0.384 AC: 1334 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	10
DANN	Benign	0.84
PhyloP100		0.077
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2242217; hg19: chr5-180040918; COSMIC: COSV56118998; COSMIC: COSV56118998;