19-8371109-C-T

Variant names:

• chr19-8371109-C-T
• rs761889493
• NM_139314.3:c.715C>T

Variant summary

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

The NM_139314.3(ANGPTL4):​c.715C>T​(p.Arg239Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000241 in 1,611,238 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: ANGPTL4 NM_139314.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.66
• 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPTL4	NM_139314.3	c.715C>T	p.Arg239Trp	missense_variant	Exon 5 of 7	ENST00000301455.7	NP_647475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPTL4	ENST00000301455.7	c.715C>T	p.Arg239Trp	missense_variant	Exon 5 of 7	1	NM_139314.3	ENSP00000301455.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000575 AC: 14 AN: 243522 AF XY: 0.0000379

Gnomad AFR exome AF: 0.0000642

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000110

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000254 AC: 371 AN: 1459044 Hom.: 0 Cov.: 31 AF XY: 0.000222 AC XY: 161 AN XY: 725626

African (AFR) AF: 0.0000598 AC: 2 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 85816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000324 AC: 360 AN: 1110760

Other (OTH) AF: 0.000149 AC: 9 AN: 60244

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74354

African (AFR) AF: 0.000121 AC: 5 AN: 41442

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000762 Hom.: 0

Bravo AF: 0.0000945

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.715C>T (p.R239W) alteration is located in exon 5 (coding exon 5) of the ANGPTL4 gene. This alteration results from a C to T substitution at nucleotide position 715, causing the arginine (R) at amino acid position 239 to be replaced by a tryptophan (W). 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	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	4.2	H;.
PhyloP100		5.7
PrimateAI	Benign	0.21	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Benign	0.19
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.58
MVP		0.77
MPC		0.74
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.79
gMVP		0.75
Mutation Taster		=54/46	polymorphism

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: rs761889493; hg19: chr19-8435993;