rs144453562

Variant names:

• chr5-180625831-TGGCTGTGCAGGGGACCTGA-T
• rs144453562
• NM_182925.5:c.1421+19_1421+37delTCAGGTCCCCTGCACAGCC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_182925.5(FLT4):​c.1421+19_1421+37delTCAGGTCCCCTGCACAGCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0279 in 1,598,372 control chromosomes in the GnomAD database, including 2,172 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (583 hom., cov: 32)
  • Exomes 𝑓: 0.024 (1589 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 5-180625831-TGGCTGTGCAGGGGACCTGA-T is Benign according to our data. Variant chr5-180625831-TGGCTGTGCAGGGGACCTGA-T is described in ClinVar as Benign. ClinVar VariationId is 263025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5	c.1421+19_1421+37delTCAGGTCCCCTGCACAGCC		intron_variant	Intron 10 of 29	ENST00000261937.11	NP_891555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLT4	ENST00000261937.11	c.1421+19_1421+37delTCAGGTCCCCTGCACAGCC		intron_variant	Intron 10 of 29	1	NM_182925.5	ENSP00000261937.6

Frequencies

GnomAD3 genomes AF: 0.0601 AC: 9134 AN: 152052 Hom.: 576 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0389

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.0332

Gnomad FIN AF: 0.0411

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.0521

GnomAD2 exomes AF: 0.0479 AC: 11413 AN: 238210 AF XY: 0.0432

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.0579

Gnomad ASJ exome AF: 0.0471

Gnomad EAS exome AF: 0.218

Gnomad FIN exome AF: 0.0362

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0389

GnomAD4 exome AF: 0.0244 AC: 35344 AN: 1446200 Hom.: 1589 AF XY: 0.0241 AC XY: 17338 AN XY: 720018

African (AFR) AF: 0.149 AC: 4935 AN: 33206

American (AMR) AF: 0.0551 AC: 2438 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.0468 AC: 1217 AN: 25994

East Asian (EAS) AF: 0.200 AC: 7927 AN: 39588

South Asian (SAS) AF: 0.0261 AC: 2237 AN: 85582

European-Finnish (FIN) AF: 0.0366 AC: 1893 AN: 51698

Middle Eastern (MID) AF: 0.0581 AC: 252 AN: 4338

European-Non Finnish (NFE) AF: 0.0111 AC: 12203 AN: 1101860

Other (OTH) AF: 0.0376 AC: 2242 AN: 59672

GnomAD4 genome AF: 0.0604 AC: 9185 AN: 152172 Hom.: 583 Cov.: 32 AF XY: 0.0623 AC XY: 4636 AN XY: 74406

African (AFR) AF: 0.139 AC: 5776 AN: 41514

American (AMR) AF: 0.0391 AC: 598 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 151 AN: 3468

East Asian (EAS) AF: 0.215 AC: 1108 AN: 5164

South Asian (SAS) AF: 0.0340 AC: 164 AN: 4820

European-Finnish (FIN) AF: 0.0411 AC: 436 AN: 10612

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0119 AC: 810 AN: 67992

Other (OTH) AF: 0.0591 AC: 125 AN: 2114

Alfa AF: 0.0381 Hom.: 44

Bravo AF: 0.0676

Asia WGS AF: 0.137 AC: 473 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 20, 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
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144453562; hg19: chr5-180052831; COSMIC: COSV56114548; COSMIC: COSV56114548;