19-8369320-A-T
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_139314.3(ANGPTL4):c.649A>T(p.Lys217*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as association (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
ANGPTL4
NM_139314.3 stop_gained
NM_139314.3 stop_gained
Scores
2
2
2
Clinical Significance
Conservation
PhyloP100: 1.60
Publications
3 publications found
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 was made for transcript
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_139314.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ANGPTL4 | NM_139314.3 | MANE Select | c.649A>T | p.Lys217* | stop_gained | Exon 4 of 7 | NP_647475.1 | Q9BY76-1 | |
| ANGPTL4 | NM_001039667.3 | c.548-1736A>T | intron | N/A | NP_001034756.1 | Q9BY76-2 | |||
| ANGPTL4 | NR_104213.2 | n.596+3256A>T | intron | N/A |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ANGPTL4 | ENST00000301455.7 | TSL:1 MANE Select | c.649A>T | p.Lys217* | stop_gained | Exon 4 of 7 | ENSP00000301455.1 | Q9BY76-1 | |
| ANGPTL4 | ENST00000593998.5 | TSL:1 | n.649A>T | non_coding_transcript_exon | Exon 4 of 8 | ENSP00000472551.1 | Q9BY76-1 | ||
| ANGPTL4 | ENST00000955923.1 | c.649A>T | p.Lys217* | stop_gained | Exon 5 of 8 | ENSP00000625982.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152114Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152114
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459482Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 725676 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1459482
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
725676
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33464
American (AMR)
AF:
AC:
0
AN:
44552
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25870
East Asian (EAS)
AF:
AC:
0
AN:
39680
South Asian (SAS)
AF:
AC:
0
AN:
85294
European-Finnish (FIN)
AF:
AC:
0
AN:
53364
Middle Eastern (MID)
AF:
AC:
0
AN:
5482
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111490
Other (OTH)
AF:
AC:
0
AN:
60286
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.00000657 AC: 1AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74308 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152114
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74308
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41432
American (AMR)
AF:
AC:
0
AN:
15242
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5194
South Asian (SAS)
AF:
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
AC:
0
AN:
10606
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68018
Other (OTH)
AF:
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:association
Revision:no assertion criteria provided
Pathogenic
VUS
Benign
Condition
-
-
-
Plasma triglyceride level quantitative trait locus (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
PhyloP100
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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