5-180616330-C-G

Variant names:

• chr5-180616330-C-G
• rs55657009
• NM_182925.5:c.3219+37G>C

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.3219+37G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0472 in 1,613,180 control chromosomes in the GnomAD database, including 2,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (161 hom., cov: 31)
  • Exomes 𝑓: 0.048 (1991 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.69
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 5-180616330-C-G is Benign according to our data. Variant chr5-180616330-C-G is described in ClinVar as Benign. ClinVar VariationId is 263045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5	c.3219+37G>C		intron_variant	Intron 23 of 29	ENST00000261937.11	NP_891555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLT4	ENST00000261937.11	c.3219+37G>C		intron_variant	Intron 23 of 29	1	NM_182925.5	ENSP00000261937.6

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5578 AN: 152230 Hom.: 161 Cov.: 31

Gnomad AFR AF: 0.00965

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.0861

Gnomad EAS AF: 0.0869

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0393

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0484

Gnomad OTH AF: 0.0353

GnomAD2 exomes AF: 0.0428 AC: 10736 AN: 250730 AF XY: 0.0431

Gnomad AFR exome AF: 0.00968

Gnomad AMR exome AF: 0.0237

Gnomad ASJ exome AF: 0.0880

Gnomad EAS exome AF: 0.0880

Gnomad FIN exome AF: 0.0368

Gnomad NFE exome AF: 0.0469

Gnomad OTH exome AF: 0.0442

GnomAD4 exome AF: 0.0483 AC: 70518 AN: 1460832 Hom.: 1991 Cov.: 31 AF XY: 0.0478 AC XY: 34774 AN XY: 726790

African (AFR) AF: 0.00768 AC: 257 AN: 33470

American (AMR) AF: 0.0250 AC: 1116 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0822 AC: 2146 AN: 26122

East Asian (EAS) AF: 0.103 AC: 4105 AN: 39694

South Asian (SAS) AF: 0.0283 AC: 2444 AN: 86240

European-Finnish (FIN) AF: 0.0378 AC: 2001 AN: 52908

Middle Eastern (MID) AF: 0.0262 AC: 151 AN: 5768

European-Non Finnish (NFE) AF: 0.0498 AC: 55400 AN: 1111552

Other (OTH) AF: 0.0480 AC: 2898 AN: 60364

GnomAD4 genome AF: 0.0366 AC: 5580 AN: 152348 Hom.: 161 Cov.: 31 AF XY: 0.0351 AC XY: 2612 AN XY: 74494

African (AFR) AF: 0.00959 AC: 399 AN: 41586

American (AMR) AF: 0.0325 AC: 497 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0861 AC: 299 AN: 3472

East Asian (EAS) AF: 0.0871 AC: 451 AN: 5180

South Asian (SAS) AF: 0.0269 AC: 130 AN: 4828

European-Finnish (FIN) AF: 0.0393 AC: 417 AN: 10622

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0484 AC: 3294 AN: 68032

Other (OTH) AF: 0.0373 AC: 79 AN: 2116

Alfa AF: 0.0303 Hom.: 27

Bravo AF: 0.0357

Asia WGS AF: 0.0530 AC: 187 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0050
DANN	Benign	0.33
PhyloP100		-3.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55657009; hg19: chr5-180043330; COSMIC: COSV56100306; COSMIC: COSV56100306;