NM_182925.5:c.1103+33A>C

Variant names:

• chr5-180628849-T-G
• rs75361132
• NM_182925.5:c.1103+33A>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.1103+33A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0335 in 1,421,056 control chromosomes in the GnomAD database, including 4,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (591 hom., cov: 33)
  • Exomes 𝑓: 0.032 (3848 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.856
• Publications: 5 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=-0.94).
• BP6: Variant 5-180628849-T-G is Benign according to our data. Variant chr5-180628849-T-G is described in ClinVar as Benign. ClinVar VariationId is 263019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.411 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.1103+33A>C		intron	N/A	NP_891555.2
	FLT4	NM_001354989.2		c.1103+33A>C		intron	N/A	NP_001341918.1
	FLT4	NM_002020.5		c.1103+33A>C		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.1103+33A>C		intron	N/A	ENSP00000261937.6
	FLT4	ENST00000502649.5	TSL:1	c.1103+33A>C		intron	N/A	ENSP00000426057.1
	FLT4	ENST00000393347.7	TSL:1	c.1103+33A>C		intron	N/A	ENSP00000377016.3

Frequencies

GnomAD3 genomes AF: 0.0463 AC: 7036 AN: 151944 Hom.: 584 Cov.: 33

Gnomad AFR AF: 0.0595

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.0674

Gnomad FIN AF: 0.0445

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.0459

GnomAD2 exomes AF: 0.0741 AC: 15573 AN: 210076 AF XY: 0.0699

Gnomad AFR exome AF: 0.0620

Gnomad AMR exome AF: 0.0613

Gnomad ASJ exome AF: 0.0627

Gnomad EAS exome AF: 0.453

Gnomad FIN exome AF: 0.0596

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0515

GnomAD4 exome AF: 0.0320 AC: 40553 AN: 1268994 Hom.: 3848 Cov.: 20 AF XY: 0.0326 AC XY: 20766 AN XY: 636564

African (AFR) AF: 0.0565 AC: 1715 AN: 30362

American (AMR) AF: 0.0560 AC: 2436 AN: 43474

Ashkenazi Jewish (ASJ) AF: 0.0492 AC: 1111 AN: 22576

East Asian (EAS) AF: 0.408 AC: 15717 AN: 38536

South Asian (SAS) AF: 0.0578 AC: 4450 AN: 76984

European-Finnish (FIN) AF: 0.0441 AC: 1875 AN: 42528

Middle Eastern (MID) AF: 0.0447 AC: 216 AN: 4834

European-Non Finnish (NFE) AF: 0.0111 AC: 10565 AN: 955690

Other (OTH) AF: 0.0457 AC: 2468 AN: 54010

GnomAD4 genome AF: 0.0465 AC: 7068 AN: 152062 Hom.: 591 Cov.: 33 AF XY: 0.0502 AC XY: 3728 AN XY: 74320

African (AFR) AF: 0.0596 AC: 2475 AN: 41510

American (AMR) AF: 0.0334 AC: 511 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 147 AN: 3470

East Asian (EAS) AF: 0.426 AC: 2181 AN: 5116

South Asian (SAS) AF: 0.0679 AC: 327 AN: 4818

European-Finnish (FIN) AF: 0.0445 AC: 471 AN: 10596

Middle Eastern (MID) AF: 0.0411 AC: 12 AN: 292

European-Non Finnish (NFE) AF: 0.0122 AC: 832 AN: 67956

Other (OTH) AF: 0.0530 AC: 112 AN: 2114

Alfa AF: 0.0331 Hom.: 94

Bravo AF: 0.0509

Asia WGS AF: 0.214 AC: 742 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	12
DANN	Benign	0.25
PhyloP100		0.86
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: rs75361132; hg19: chr5-180055849; COSMIC: COSV56099894; COSMIC: COSV56099894;