5-180618739-A-C

Variant names:

• chr5-180618739-A-C
• rs201575824
• NM_182925.5:c.3001+31T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_182925.5(FLT4):​c.3001+31T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00695 in 1,575,062 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (42 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.65
• Publications: 0 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=-0.96).
• BP6: Variant 5-180618739-A-C is Benign according to our data. Variant chr5-180618739-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 263041.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00449 (684/152220) while in subpopulation NFE AF = 0.00754 (513/67996). AF 95% confidence interval is 0.007. There are 2 homozygotes in GnomAd4. There are 315 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 684 AD gene.

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.3001+31T>G		intron	N/A	NP_891555.2
	FLT4	NM_001354989.2		c.3001+31T>G		intron	N/A	NP_001341918.1
	FLT4	NM_002020.5		c.3001+31T>G		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.3001+31T>G		intron	N/A	ENSP00000261937.6
	FLT4	ENST00000502649.5	TSL:1	c.3001+31T>G		intron	N/A	ENSP00000426057.1
	FLT4	ENST00000393347.7	TSL:1	c.3001+31T>G		intron	N/A	ENSP00000377016.3

Frequencies

GnomAD3 genomes AF: 0.00450 AC: 684 AN: 152102 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00359

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00754

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00424 AC: 777 AN: 183450 AF XY: 0.00439

Gnomad AFR exome AF: 0.000477

Gnomad AMR exome AF: 0.00248

Gnomad ASJ exome AF: 0.00418

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00421

Gnomad NFE exome AF: 0.00667

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00722 AC: 10269 AN: 1422842 Hom.: 42 Cov.: 34 AF XY: 0.00718 AC XY: 5059 AN XY: 704684

African (AFR) AF: 0.000740 AC: 24 AN: 32424

American (AMR) AF: 0.00244 AC: 97 AN: 39764

Ashkenazi Jewish (ASJ) AF: 0.00463 AC: 118 AN: 25498

East Asian (EAS) AF: 0.00 AC: 0 AN: 37240

South Asian (SAS) AF: 0.00287 AC: 233 AN: 81160

European-Finnish (FIN) AF: 0.00417 AC: 204 AN: 48892

Middle Eastern (MID) AF: 0.00333 AC: 19 AN: 5714

European-Non Finnish (NFE) AF: 0.00843 AC: 9217 AN: 1093222

Other (OTH) AF: 0.00606 AC: 357 AN: 58928

GnomAD4 genome AF: 0.00449 AC: 684 AN: 152220 Hom.: 2 Cov.: 33 AF XY: 0.00423 AC XY: 315 AN XY: 74420

African (AFR) AF: 0.00159 AC: 66 AN: 41552

American (AMR) AF: 0.00262 AC: 40 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.00359 AC: 38 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00754 AC: 513 AN: 67996

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00656 Hom.: 1

Bravo AF: 0.00435

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.54
DANN	Benign	0.43
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism

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: rs201575824; hg19: chr5-180045739;