chr5-180649460-G-C

Variant names:

• chr5-180649460-G-C
• rs147801168
• NM_182925.5:c.58+28C>G

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.58+28C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00583 in 1,447,678 control chromosomes in the GnomAD database, including 336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (171 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (165 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.288
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-180649460-G-C is Benign according to our data. Variant chr5-180649460-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0875 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.58+28C>G		intron	N/A	NP_891555.2
	FLT4	NM_001354989.2		c.58+28C>G		intron	N/A	NP_001341918.1
	FLT4	NM_002020.5		c.58+28C>G		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.58+28C>G		intron	N/A	ENSP00000261937.6
	FLT4	ENST00000502649.5	TSL:1	c.58+28C>G		intron	N/A	ENSP00000426057.1
	FLT4	ENST00000393347.7	TSL:1	c.58+28C>G		intron	N/A	ENSP00000377016.3

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 4041 AN: 151752 Hom.: 170 Cov.: 33

Gnomad AFR AF: 0.0898

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0000957

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.00381 AC: 306 AN: 80248 AF XY: 0.00297

Gnomad AFR exome AF: 0.0989

Gnomad AMR exome AF: 0.00512

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00470

GnomAD4 exome AF: 0.00339 AC: 4387 AN: 1295818 Hom.: 165 Cov.: 28 AF XY: 0.00314 AC XY: 2006 AN XY: 639374

African (AFR) AF: 0.0975 AC: 2536 AN: 26000

American (AMR) AF: 0.00692 AC: 184 AN: 26580

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 232 AN: 22366

East Asian (EAS) AF: 0.00 AC: 0 AN: 27206

South Asian (SAS) AF: 0.000885 AC: 64 AN: 72284

European-Finnish (FIN) AF: 0.000124 AC: 4 AN: 32300

Middle Eastern (MID) AF: 0.0214 AC: 81 AN: 3786

European-Non Finnish (NFE) AF: 0.000861 AC: 889 AN: 1032172

Other (OTH) AF: 0.00747 AC: 397 AN: 53124

GnomAD4 genome AF: 0.0267 AC: 4058 AN: 151860 Hom.: 171 Cov.: 33 AF XY: 0.0257 AC XY: 1911 AN XY: 74234

African (AFR) AF: 0.0899 AC: 3731 AN: 41492

American (AMR) AF: 0.0106 AC: 161 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.0000957 AC: 1 AN: 10452

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 67894

Other (OTH) AF: 0.0185 AC: 39 AN: 2106

Alfa AF: 0.0152 Hom.: 14

Bravo AF: 0.0307

Asia WGS AF: 0.00654 AC: 22 AN: 3378

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely 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	-0.76
CADD	Benign	2.5
DANN	Benign	0.53
PhyloP100		-0.29
PromoterAI		-0.0084	Neutral
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: rs147801168; hg19: chr5-180076460;