chr5-180607823-T-C

Variant names:

• chr5-180607823-T-C
• rs1049095
• NM_182925.5:c.3893+1145A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182925.5(FLT4):​c.3893+1145A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 456,178 control chromosomes in the GnomAD database, including 22,723 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (7124 hom., cov: 31)
  • Exomes 𝑓: 0.31 (15599 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.83
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.349 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.3893+1145A>G		intron	N/A	NP_891555.2
	FLT4	NM_001354989.2		c.*309A>G		3_prime_UTR	Exon 30 of 30	NP_001341918.1
	FLT4	NM_002020.5		c.*458A>G		3_prime_UTR	Exon 30 of 30	NP_002011.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	ENST00000261937.11	TSL:1 MANE Select	c.3893+1145A>G		intron	N/A	ENSP00000261937.6
	FLT4	ENST00000502603.5	TSL:2	n.593+1145A>G		intron	N/A
	FLT4	ENST00000502649.5	TSL:1	c.*309A>G		downstream_gene	N/A	ENSP00000426057.1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45898 AN: 151862 Hom.: 7124 Cov.: 31

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.310

GnomAD4 exome AF: 0.313 AC: 95247 AN: 304198 Hom.: 15599 AF XY: 0.317 AC XY: 49683 AN XY: 156606

African (AFR) AF: 0.264 AC: 2721 AN: 10304

American (AMR) AF: 0.218 AC: 2489 AN: 11400

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 3910 AN: 10324

East Asian (EAS) AF: 0.330 AC: 7442 AN: 22558

South Asian (SAS) AF: 0.348 AC: 8009 AN: 22982

European-Finnish (FIN) AF: 0.248 AC: 4333 AN: 17482

Middle Eastern (MID) AF: 0.389 AC: 552 AN: 1418

European-Non Finnish (NFE) AF: 0.317 AC: 59808 AN: 188802

Other (OTH) AF: 0.316 AC: 5983 AN: 18928

GnomAD4 genome AF: 0.302 AC: 45907 AN: 151980 Hom.: 7124 Cov.: 31 AF XY: 0.300 AC XY: 22291 AN XY: 74296

African (AFR) AF: 0.266 AC: 11020 AN: 41444

American (AMR) AF: 0.260 AC: 3966 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1411 AN: 3472

East Asian (EAS) AF: 0.343 AC: 1765 AN: 5152

South Asian (SAS) AF: 0.363 AC: 1747 AN: 4812

European-Finnish (FIN) AF: 0.261 AC: 2753 AN: 10564

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22264 AN: 67962

Other (OTH) AF: 0.310 AC: 653 AN: 2106

Alfa AF: 0.311 Hom.: 922

Bravo AF: 0.299

Asia WGS AF: 0.326 AC: 1137 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.21
DANN	Benign	0.21
PhyloP100		-4.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1049095; hg19: chr5-180034823;