chr5-180622808-T-C

Position:

• chr5-180622808-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182925.5(FLT4):​c.1580A>G​(p.Asn527Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00445 in 1,613,484 control chromosomes in the GnomAD database, including 292 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N527D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (139 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (153 hom.)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.13

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020684302).
• BP6: Variant 5-180622808-T-C is Benign according to our data. Variant chr5-180622808-T-C is described in ClinVar as [Benign]. Clinvar id is 263029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-180622808-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT4	NM_182925.5	c.1580A>G	p.Asn527Ser	missense_variant	12/30	ENST00000261937.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT4	ENST00000261937.11	c.1580A>G	p.Asn527Ser	missense_variant	12/30	1	NM_182925.5	P1

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3554 AN: 152102 Hom.: 139 Cov.: 32

Gnomad AFR AF: 0.0816

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00760

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00591 AC: 1482 AN: 250658 Hom.: 57 AF XY: 0.00438 AC XY: 595 AN XY: 135780

Gnomad AFR exome AF: 0.0822

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00248 AC: 3619 AN: 1461264 Hom.: 153 Cov.: 31 AF XY: 0.00215 AC XY: 1562 AN XY: 726916

Gnomad4 AFR exome AF: 0.0888

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000980

Gnomad4 OTH exome AF: 0.00547

GnomAD4 genome AF: 0.0234 AC: 3564 AN: 152220 Hom.: 139 Cov.: 32 AF XY: 0.0228 AC XY: 1694 AN XY: 74432

Gnomad4 AFR AF: 0.0816

Gnomad4 AMR AF: 0.00759

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00530 Hom.: 24

Bravo AF: 0.0271

ESP6500AA AF: 0.0817 AC: 360

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00733 AC: 890

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.067
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D;D;D
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.73	T;T;T
Polyphen		0.12	B;.;B
Vest4		0.23
MVP		0.37
MPC		0.81
ClinPred		0.029	T
GERP RS		4.2
Varity_R		0.23
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs35874891; hg19: chr5-180049808;