rs59410886

Variant names:

• chr5-180630538-C-T
• rs59410886
• NM_182925.5:c.400+17G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182925.5(FLT4):​c.400+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,612,380 control chromosomes in the GnomAD database, including 3,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (434 hom., cov: 32)
  • Exomes 𝑓: 0.018 (3104 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.51
• 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):

• 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: Ambry Genetics, G2P, ClinGen, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-180630538-C-T is Benign according to our data. Variant chr5-180630538-C-T is described in ClinVar as Benign. ClinVar VariationId is 263058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 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.400+17G>A		intron	N/A	NP_891555.2	P35916-2
	FLT4	NM_001354989.2		c.400+17G>A		intron	N/A	NP_001341918.1	E9PD35
	FLT4	NM_002020.5		c.400+17G>A		intron	N/A	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.400+17G>A		intron	N/A	ENSP00000261937.6	P35916-2
	FLT4	ENST00000502649.5	TSL:1	c.400+17G>A		intron	N/A	ENSP00000426057.1	E9PD35
	FLT4	ENST00000393347.7	TSL:1	c.400+17G>A		intron	N/A	ENSP00000377016.3	P35916-1

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3402 AN: 152044 Hom.: 428 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.0260

Gnomad FIN AF: 0.0428

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.0240

GnomAD2 exomes AF: 0.0490 AC: 12137 AN: 247934 AF XY: 0.0450

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.0573

Gnomad ASJ exome AF: 0.0291

Gnomad EAS exome AF: 0.429

Gnomad FIN exome AF: 0.0416

Gnomad NFE exome AF: 0.00474

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0180 AC: 26319 AN: 1460218 Hom.: 3104 Cov.: 35 AF XY: 0.0179 AC XY: 12995 AN XY: 726416

African (AFR) AF: 0.00218 AC: 73 AN: 33472

American (AMR) AF: 0.0513 AC: 2294 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0281 AC: 734 AN: 26122

East Asian (EAS) AF: 0.377 AC: 14950 AN: 39638

South Asian (SAS) AF: 0.0162 AC: 1394 AN: 86232

European-Finnish (FIN) AF: 0.0392 AC: 2040 AN: 52068

Middle Eastern (MID) AF: 0.0291 AC: 168 AN: 5768

European-Non Finnish (NFE) AF: 0.00268 AC: 2981 AN: 1111874

Other (OTH) AF: 0.0279 AC: 1685 AN: 60356

GnomAD4 genome AF: 0.0225 AC: 3421 AN: 152162 Hom.: 434 Cov.: 32 AF XY: 0.0266 AC XY: 1980 AN XY: 74388

African (AFR) AF: 0.00161 AC: 67 AN: 41522

American (AMR) AF: 0.0222 AC: 340 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 91 AN: 3472

East Asian (EAS) AF: 0.399 AC: 2039 AN: 5116

South Asian (SAS) AF: 0.0263 AC: 127 AN: 4834

European-Finnish (FIN) AF: 0.0428 AC: 454 AN: 10610

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00344 AC: 234 AN: 67996

Other (OTH) AF: 0.0304 AC: 64 AN: 2106

Alfa AF: 0.0153 Hom.: 28

Bravo AF: 0.0266

Asia WGS AF: 0.169 AC: 585 AN: 3478

ClinVar

ClinVar submissions

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	-0.87
CADD	Benign	0.38
DANN	Benign	0.69
PhyloP100		-1.5
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs59410886;

hg19: chr5-180057538;

COSMIC: COSV56099905;

COSMIC: COSV56099905;