5-180630356-C-G

Variant names:

• chr5-180630356-C-G
• rs56188706
• NM_182925.5:c.401-19G>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.401-19G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,601,888 control chromosomes in the GnomAD database, including 13,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1527 hom., cov: 32)
  • Exomes 𝑓: 0.10 (11777 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0790
• 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=-0.85).
• BP6: Variant 5-180630356-C-G is Benign according to our data. Variant chr5-180630356-C-G is described in ClinVar as Benign. ClinVar VariationId is 263060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5	c.401-19G>C		intron_variant	Intron 3 of 29	ENST00000261937.11	NP_891555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLT4	ENST00000261937.11	c.401-19G>C		intron_variant	Intron 3 of 29	1	NM_182925.5	ENSP00000261937.6

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17120 AN: 152016 Hom.: 1520 Cov.: 32

Gnomad AFR AF: 0.0919

Gnomad AMI AF: 0.00881

Gnomad AMR AF: 0.0811

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.0873

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0904

Gnomad OTH AF: 0.104

GnomAD2 exomes AF: 0.131 AC: 31944 AN: 243052 AF XY: 0.127

Gnomad AFR exome AF: 0.0982

Gnomad AMR exome AF: 0.0880

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.559

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.0852

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.101 AC: 146580 AN: 1449752 Hom.: 11777 Cov.: 33 AF XY: 0.101 AC XY: 72671 AN XY: 721684

African (AFR) AF: 0.0936 AC: 3126 AN: 33396

American (AMR) AF: 0.0857 AC: 3828 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 4337 AN: 26110

East Asian (EAS) AF: 0.528 AC: 20945 AN: 39660

South Asian (SAS) AF: 0.0808 AC: 6958 AN: 86158

European-Finnish (FIN) AF: 0.161 AC: 7265 AN: 45242

Middle Eastern (MID) AF: 0.0722 AC: 416 AN: 5758

European-Non Finnish (NFE) AF: 0.0837 AC: 92775 AN: 1108546

Other (OTH) AF: 0.115 AC: 6930 AN: 60206

GnomAD4 genome AF: 0.113 AC: 17152 AN: 152136 Hom.: 1527 Cov.: 32 AF XY: 0.117 AC XY: 8688 AN XY: 74358

African (AFR) AF: 0.0921 AC: 3823 AN: 41518

American (AMR) AF: 0.0811 AC: 1241 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 591 AN: 3472

East Asian (EAS) AF: 0.532 AC: 2732 AN: 5140

South Asian (SAS) AF: 0.0880 AC: 424 AN: 4820

European-Finnish (FIN) AF: 0.183 AC: 1933 AN: 10588

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.0904 AC: 6147 AN: 67994

Other (OTH) AF: 0.112 AC: 236 AN: 2110

Alfa AF: 0.0812 Hom.: 136

Bravo AF: 0.109

Asia WGS AF: 0.282 AC: 981 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	-0.85
CADD	Benign	1.9
DANN	Benign	0.37
PhyloP100		0.079
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: rs56188706; hg19: chr5-180057356; COSMIC: COSV56099334;