19-8371418-T-G

Variant names:

• chr19-8371418-T-G
• NM_139314.3:c.935T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_139314.3(ANGPTL4):​c.935T>G​(p.Leu312Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANGPTL4 NM_139314.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.77
• Publications: 0 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]

RAB11B-AS1 (HGNC:44178): (RAB11B antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPTL4	NM_139314.3	c.935T>G	p.Leu312Arg	missense_variant	Exon 6 of 7	ENST00000301455.7	NP_647475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPTL4	ENST00000301455.7	c.935T>G	p.Leu312Arg	missense_variant	Exon 6 of 7	1	NM_139314.3	ENSP00000301455.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.935T>G (p.L312R) alteration is located in exon 6 (coding exon 6) of the ANGPTL4 gene. This alteration results from a T to G substitution at nucleotide position 935, causing the leucine (L) at amino acid position 312 to be replaced by an arginine (R). 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	0.15
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.76	.;T
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.
PhyloP100		3.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.97	D;.
Vest4		0.76
MutPred		0.68		Gain of methylation at L312 (P = 0.0194);.;
MVP		0.63
MPC		0.93
ClinPred		0.93	D
GERP RS		4.1
Varity_R		0.55
gMVP		0.86
Mutation Taster		=33/67	disease causing

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

hg19: chr19-8436302;