chr19-8364439-G-A

Position:

• chr19-8364439-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_139314.3(ANGPTL4):​c.118G>A​(p.Glu40Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0171 in 1,555,220 control chromosomes in the GnomAD database, including 262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars). Synonymous variant affecting the same amino acid position (i.e. E40E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (30 hom., cov: 32)
  • Exomes 𝑓: 0.017 (232 hom.)
• Consequence: ANGPTL4 NM_139314.3 missense
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 6.58

Genes affected

ANGPTL4 (HGNC:16039): (angiopoietin like 4) This gene encodes a glycosylated, secreted protein containing a C-terminal fibrinogen domain. The encoded protein is induced by peroxisome proliferation activators and functions as a serum hormone that regulates glucose homeostasis, lipid metabolism, and insulin sensitivity. This protein can also act as an apoptosis survival factor for vascular endothelial cells and can prevent metastasis by inhibiting vascular growth and tumor cell invasion. The C-terminal domain may be proteolytically-cleaved from the full-length secreted protein. Decreased expression of this gene has been associated with type 2 diabetes. Alternative splicing results in multiple transcript variants. This gene was previously referred to as ANGPTL2 but has been renamed ANGPTL4. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040303767).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.015 (2292/152350) while in subpopulation AMR AF= 0.0236 (361/15308). AF 95% confidence interval is 0.0216. There are 30 homozygotes in gnomad4. There are 1095 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 30 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPTL4	NM_139314.3	c.118G>A	p.Glu40Lys	missense_variant	1/7	ENST00000301455.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANGPTL4	ENST00000301455.7	c.118G>A	p.Glu40Lys	missense_variant	1/7	1	NM_139314.3	P1

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2292 AN: 152232 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0206

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.0133 AC: 2016 AN: 151260 Hom.: 17 AF XY: 0.0130 AC XY: 1068 AN XY: 82292

Gnomad AFR exome AF: 0.00316

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000649

Gnomad FIN exome AF: 0.0257

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.0174 AC: 24354 AN: 1402870 Hom.: 232 Cov.: 32 AF XY: 0.0171 AC XY: 11879 AN XY: 693090

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.0129

Gnomad4 ASJ exome AF: 0.0154

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000763

Gnomad4 FIN exome AF: 0.0260

Gnomad4 NFE exome AF: 0.0196

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome AF: 0.0150 AC: 2292 AN: 152350 Hom.: 30 Cov.: 32 AF XY: 0.0147 AC XY: 1095 AN XY: 74496

Gnomad4 AFR AF: 0.00293

Gnomad4 AMR AF: 0.0236

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0254

Gnomad4 NFE AF: 0.0207

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0191 Hom.: 50

Bravo AF: 0.0146

ESP6500AA AF: 0.000953 AC: 4

ESP6500EA AF: 0.0160 AC: 132

ExAC AF: 0.00807 AC: 918

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Plasma triglyceride level quantitative trait locus Other:1

association, no assertion criteria provided

literature only

OMIM

May 08, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	.;.;T;T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;D;.;D
MetaRNN	Benign	0.0040	T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.7	.;.;.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.1	.;.;.;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.010	.;.;.;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D
Polyphen		1.0	.;.;.;D;.
Vest4		0.39, 0.34
MPC		0.81
ClinPred		0.036	T
GERP RS		5.0
Varity_R		0.30
gMVP		0.73

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: rs116843064; hg19: chr19-8429323; COSMIC: COSV99041543;