19-8364522-C-G

Variant names:

• chr19-8364522-C-G
• rs538554190
• NM_139314.3:c.201C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_139314.3(ANGPTL4):​c.201C>G​(p.Ser67Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000351 in 1,566,318 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (6 hom.)
• Consequence: ANGPTL4 NM_139314.3 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.06

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069996417).
• BP6: Variant 19-8364522-C-G is Benign according to our data. Variant chr19-8364522-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3042507.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPTL4	NM_139314.3	c.201C>G	p.Ser67Arg	missense_variant	Exon 1 of 7	ENST00000301455.7	NP_647475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPTL4	ENST00000301455.7	c.201C>G	p.Ser67Arg	missense_variant	Exon 1 of 7	1	NM_139314.3	ENSP00000301455.1

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000842 AC: 138 AN: 163990 AF XY: 0.00111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000157

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.000359 AC: 508 AN: 1413982 Hom.: 6 Cov.: 32 AF XY: 0.000514 AC XY: 359 AN XY: 699090

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 32524

Gnomad4 AMR exome AF: 0.000106 AC: 4 AN: 37664

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25218

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 37184

Gnomad4 SAS exome AF: 0.00589 AC: 475 AN: 80586

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 48706

Gnomad4 NFE exome AF: 0.00000367 AC: 4 AN: 1088720

Gnomad4 Remaining exome AF: 0.000427 AC: 25 AN: 58502

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000456 AC XY: 34 AN XY: 74494

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00870 AC: 0.00869565 AN: 0.00869565

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000540 AC: 63

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ANGPTL4-related disorder Benign:1

Jul 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.63
DEOGEN2	Benign	0.0045	.;.;T;T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.59	T;T;T;.;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.0070	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.40	.;.;.;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.020	.;.;.;N;N
REVEL	Benign	0.073
Sift	Benign	0.75	.;.;.;T;T
Sift4G	Benign	0.89	T;T;T;T;T
Polyphen		0.0	.;.;.;B;.
Vest4		0.057, 0.085
MutPred		0.12		Gain of MoRF binding (P = 0.016);Gain of MoRF binding (P = 0.016);Gain of MoRF binding (P = 0.016);Gain of MoRF binding (P = 0.016);Gain of MoRF binding (P = 0.016);
MVP		0.69
MPC		0.22
ClinPred		0.011	T
GERP RS		0.62
Varity_R		0.15
gMVP		0.16
Mutation Taster		=95/5	polymorphism

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: rs538554190; hg19: chr19-8429406;