19-8364506-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_139314.3(ANGPTL4):​c.185C>T​(p.Thr62Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000192 in 1,564,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T62T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ANGPTL4
NM_139314.3 missense

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.02
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANGPTL4NM_139314.3 linkc.185C>T p.Thr62Ile missense_variant Exon 1 of 7 ENST00000301455.7 NP_647475.1 Q9BY76-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANGPTL4ENST00000301455.7 linkc.185C>T p.Thr62Ile missense_variant Exon 1 of 7 1 NM_139314.3 ENSP00000301455.1 Q9BY76-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152254
Hom.:
0
Cov.:
32
show subpopulations
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
7.08e-7
AC:
1
AN:
1412096
Hom.:
0
Cov.:
32
AF XY:
0.00000143
AC XY:
1
AN XY:
698030
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:
9.19e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152254
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 27, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.185C>T (p.T62I) alteration is located in exon 1 (coding exon 1) of the ANGPTL4 gene. This alteration results from a C to T substitution at nucleotide position 185, causing the threonine (T) at amino acid position 62 to be replaced by an isoleucine (I). 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
Uncertain
0.53
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.19
.;.;T;T;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.79
T;T;T;.;T
M_CAP
Pathogenic
0.57
D
MetaRNN
Uncertain
0.68
D;D;D;D;D
MetaSVM
Benign
-0.57
T
MutationAssessor
Pathogenic
3.1
.;.;.;M;M
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-3.7
.;.;.;D;D
REVEL
Uncertain
0.30
Sift
Uncertain
0.016
.;.;.;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
0.98
.;.;.;D;.
Vest4
0.42, 0.45
MutPred
0.42
Loss of phosphorylation at T62 (P = 0.0407);Loss of phosphorylation at T62 (P = 0.0407);Loss of phosphorylation at T62 (P = 0.0407);Loss of phosphorylation at T62 (P = 0.0407);Loss of phosphorylation at T62 (P = 0.0407);
MVP
0.91
MPC
0.71
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.36
gMVP
0.86

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1279159853; hg19: chr19-8429390; API