5-180626097-C-T

Variant names:

• chr5-180626097-C-T
• rs56193546
• NM_182925.5:c.1258+14G>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.1258+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0408 in 1,612,718 control chromosomes in the GnomAD database, including 1,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (210 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1789 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.277
• Publications: 7 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=-0.88).
• BP6: Variant 5-180626097-C-T is Benign according to our data. Variant chr5-180626097-C-T is described in ClinVar as Benign. ClinVar VariationId is 263021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5	c.1258+14G>A		intron_variant	Intron 9 of 29	ENST00000261937.11	NP_891555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLT4	ENST00000261937.11	c.1258+14G>A		intron_variant	Intron 9 of 29	1	NM_182925.5	ENSP00000261937.6

Frequencies

GnomAD3 genomes AF: 0.0443 AC: 6744 AN: 152120 Hom.: 208 Cov.: 33

Gnomad AFR AF: 0.0516

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0302

Gnomad ASJ AF: 0.0931

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.0891

Gnomad FIN AF: 0.0220

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0310

Gnomad OTH AF: 0.0417

GnomAD2 exomes AF: 0.0528 AC: 13138 AN: 249044 AF XY: 0.0541

Gnomad AFR exome AF: 0.0517

Gnomad AMR exome AF: 0.0312

Gnomad ASJ exome AF: 0.0918

Gnomad EAS exome AF: 0.182

Gnomad FIN exome AF: 0.0214

Gnomad NFE exome AF: 0.0322

Gnomad OTH exome AF: 0.0529

GnomAD4 exome AF: 0.0404 AC: 59031 AN: 1460480 Hom.: 1789 Cov.: 34 AF XY: 0.0416 AC XY: 30191 AN XY: 726526

African (AFR) AF: 0.0504 AC: 1688 AN: 33480

American (AMR) AF: 0.0320 AC: 1430 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0903 AC: 2359 AN: 26132

East Asian (EAS) AF: 0.178 AC: 7052 AN: 39700

South Asian (SAS) AF: 0.0829 AC: 7148 AN: 86256

European-Finnish (FIN) AF: 0.0229 AC: 1193 AN: 52070

Middle Eastern (MID) AF: 0.0536 AC: 309 AN: 5768

European-Non Finnish (NFE) AF: 0.0314 AC: 34867 AN: 1111980

Other (OTH) AF: 0.0494 AC: 2985 AN: 60374

GnomAD4 genome AF: 0.0444 AC: 6753 AN: 152238 Hom.: 210 Cov.: 33 AF XY: 0.0449 AC XY: 3339 AN XY: 74434

African (AFR) AF: 0.0517 AC: 2147 AN: 41550

American (AMR) AF: 0.0301 AC: 461 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0931 AC: 323 AN: 3470

East Asian (EAS) AF: 0.183 AC: 946 AN: 5170

South Asian (SAS) AF: 0.0886 AC: 427 AN: 4822

European-Finnish (FIN) AF: 0.0220 AC: 234 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0310 AC: 2108 AN: 67996

Other (OTH) AF: 0.0427 AC: 90 AN: 2110

Alfa AF: 0.0412 Hom.: 51

Bravo AF: 0.0466

Asia WGS AF: 0.113 AC: 391 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

Nov 11, 2018

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	-0.88
CADD	Benign	2.8
DANN	Benign	0.53
PhyloP100		-0.28
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: rs56193546; hg19: chr5-180053097; COSMIC: COSV56110051; COSMIC: COSV56110051;