Genetic Variant NM_139314.3:c.548G>T (chr19-8369219-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_139314.3(ANGPTL4):c.548G>T(p.Arg183Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ANGPTL4
NM_139314.3 missense, splice_region

Scores

Splicing: ADA: 0.05593

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.854

Variant links:

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]

ANGPTL4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1388228).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPTL4	NM_139314.3 link	c.548G>T	p.Arg183Leu	missense_variant, splice_region_variant	Exon 4 of 7	ENST00000301455.7	NP_647475.1	Q9BY76-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPTL4	ENST00000301455.7 link	c.548G>T	p.Arg183Leu	missense_variant, splice_region_variant	Exon 4 of 7	1	NM_139314.3	ENSP00000301455.1		Q9BY76-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457462

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724590

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.548G>T (p.R183L) alteration is located in exon 4 (coding exon 4) of the ANGPTL4 gene. This alteration results from a G to T substitution at nucleotide position 548, causing the arginine (R) at amino acid position 183 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.043

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.80

M_CAP

Benign

0.010

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.65

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.5

REVEL

Benign

0.086

Sift

Benign

0.17

Sift4G

Benign

0.29

Polyphen

0.0080

Vest4

0.38

MutPred

0.36

Loss of MoRF binding (P = 0.0485);

MVP

0.44

MPC

0.32

ClinPred

0.23

GERP RS

0.91

Varity_R

0.11

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.056

dbscSNV1_RF

Benign

0.43

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over