chr19-8371316-G-A

Position:

• chr19-8371316-G-A

Variant summary

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

The NM_139314.3(ANGPTL4):​c.833G>A​(p.Arg278Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,613,846 control chromosomes in the GnomAD database, including 204 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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.

• Frequency:
  • Genomes: 𝑓 0.019 (89 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (115 hom.)
• Consequence: ANGPTL4 NM_139314.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.51

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005083561).
• BP6: Variant 19-8371316-G-A is Benign according to our data. Variant chr19-8371316-G-A is described in ClinVar as [Benign]. Clinvar id is 768962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPTL4	NM_139314.3	c.833G>A	p.Arg278Gln	missense_variant	6/7	ENST00000301455.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANGPTL4	ENST00000301455.7	c.833G>A	p.Arg278Gln	missense_variant	6/7	1	NM_139314.3	P1

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2817 AN: 152176 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00751 AC: 1882 AN: 250742 Hom.: 43 AF XY: 0.00680 AC XY: 922 AN XY: 135678

Gnomad AFR exome AF: 0.0620

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0173

Gnomad SAS exome AF: 0.0137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00298 AC: 4358 AN: 1461552 Hom.: 115 Cov.: 34 AF XY: 0.00315 AC XY: 2294 AN XY: 727108

Gnomad4 AFR exome AF: 0.0655

Gnomad4 AMR exome AF: 0.00302

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00821

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.00585

GnomAD4 genome AF: 0.0186 AC: 2832 AN: 152294 Hom.: 89 Cov.: 32 AF XY: 0.0179 AC XY: 1334 AN XY: 74464

Gnomad4 AFR AF: 0.0613

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0184

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00388 Hom.: 19

Bravo AF: 0.0213

ESP6500AA AF: 0.0570 AC: 251

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00859 AC: 1043

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 21, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.7
DANN	Benign	0.92
DEOGEN2	Benign	0.026	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.56	.;T
MetaRNN	Benign	0.0051	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	1.5	N;N
REVEL	Benign	0.12
Sift	Benign	0.98	T;T
Sift4G	Benign	0.64	T;T
Polyphen		0.017	B;.
Vest4		0.058
MVP		0.60
MPC		0.23
ClinPred		0.0029	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.069
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35061979; hg19: chr19-8436200;