19-8364115-C-T

Variant names:

• chr19-8364115-C-T
• rs4076317
• ENST00000599192.5:c.-116-91C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000599192.5(ANGPTL4):​c.-116-91C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 580,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: ANGPTL4 ENST00000599192.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.519
• Publications: 22 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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000599192.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPTL4	NM_139314.3	MANE Select	c.-207C>T		upstream_gene	N/A	NP_647475.1
	ANGPTL4	NM_001039667.3		c.-207C>T		upstream_gene	N/A	NP_001034756.1
	ANGPTL4	NR_104213.2		n.-40C>T		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPTL4	ENST00000599192.5	TSL:4	c.-116-91C>T		intron	N/A	ENSP00000473090.1
	ANGPTL4	ENST00000601886.1	TSL:5	c.-116-91C>T		intron	N/A	ENSP00000470307.1
	ANGPTL4	ENST00000601770.1	TSL:4	c.-116-91C>T		intron	N/A	ENSP00000471345.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151488 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000233 AC: 1 AN: 429292 Hom.: 0 Cov.: 5 AF XY: 0.00000447 AC XY: 1 AN XY: 223946

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 11470

American (AMR) AF: 0.00 AC: 0 AN: 16680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12724

East Asian (EAS) AF: 0.0000352 AC: 1 AN: 28446

South Asian (SAS) AF: 0.00 AC: 0 AN: 40592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1834

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 264806

Other (OTH) AF: 0.00 AC: 0 AN: 24776

⚠️ 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.

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151488 Hom.: 0 Cov.: 28 AF XY: 0.0000135 AC XY: 1 AN XY: 73918

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41272

American (AMR) AF: 0.0000658 AC: 1 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67874

Other (OTH) AF: 0.00 AC: 0 AN: 2064

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 393

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.2
DANN	Benign	0.87
PhyloP100		-0.52
PromoterAI		-0.15	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4076317; hg19: chr19-8428999;