chr5-180629863-C-T

Variant names:

• chr5-180629863-C-T
• rs56361806
• NM_182925.5:c.677-28G>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.677-28G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0359 in 1,612,426 control chromosomes in the GnomAD database, including 1,161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (151 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1010 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.00
• Publications: 4 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=-0.93).
• BP6: Variant 5-180629863-C-T is Benign according to our data. Variant chr5-180629863-C-T is described in ClinVar as Benign. ClinVar VariationId is 263070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0631 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.677-28G>A		intron	N/A	NP_891555.2
	FLT4	NM_001354989.2		c.677-28G>A		intron	N/A	NP_001341918.1
	FLT4	NM_002020.5		c.677-28G>A		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.677-28G>A		intron	N/A	ENSP00000261937.6
	FLT4	ENST00000502649.5	TSL:1	c.677-28G>A		intron	N/A	ENSP00000426057.1
	FLT4	ENST00000393347.7	TSL:1	c.677-28G>A		intron	N/A	ENSP00000377016.3

Frequencies

GnomAD3 genomes AF: 0.0422 AC: 6416 AN: 152190 Hom.: 150 Cov.: 33

Gnomad AFR AF: 0.0651

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0298

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.0397

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0368

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0313 AC: 7783 AN: 248412 AF XY: 0.0313

Gnomad AFR exome AF: 0.0675

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.0303

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0362

Gnomad NFE exome AF: 0.0374

Gnomad OTH exome AF: 0.0378

GnomAD4 exome AF: 0.0352 AC: 51415 AN: 1460118 Hom.: 1010 Cov.: 39 AF XY: 0.0348 AC XY: 25256 AN XY: 726284

African (AFR) AF: 0.0682 AC: 2281 AN: 33458

American (AMR) AF: 0.0183 AC: 819 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 769 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39682

South Asian (SAS) AF: 0.0208 AC: 1788 AN: 86168

European-Finnish (FIN) AF: 0.0369 AC: 1922 AN: 52130

Middle Eastern (MID) AF: 0.0652 AC: 376 AN: 5768

European-Non Finnish (NFE) AF: 0.0371 AC: 41192 AN: 1111748

Other (OTH) AF: 0.0375 AC: 2266 AN: 60352

GnomAD4 genome AF: 0.0422 AC: 6427 AN: 152308 Hom.: 151 Cov.: 33 AF XY: 0.0424 AC XY: 3157 AN XY: 74462

African (AFR) AF: 0.0651 AC: 2708 AN: 41568

American (AMR) AF: 0.0298 AC: 456 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4828

European-Finnish (FIN) AF: 0.0397 AC: 422 AN: 10618

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0368 AC: 2506 AN: 68022

Other (OTH) AF: 0.0317 AC: 67 AN: 2114

Alfa AF: 0.0344 Hom.: 137

Bravo AF: 0.0427

Asia WGS AF: 0.0150 AC: 54 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.032
DANN	Benign	0.71
PhyloP100		-2.0
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

Other links and lift over

dbSNP: rs56361806; hg19: chr5-180056863; COSMIC: COSV56108162;