19-8369216-C-T

Variant names:

• chr19-8369216-C-T
• rs34600793
• NM_139314.3:c.548-3C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_139314.3(ANGPTL4):​c.548-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,608,750 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (46 hom.)
• Consequence: ANGPTL4 NM_139314.3 splice_region, intron
• Scores: Splicing: ADA: 0.01186
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.24
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 19-8369216-C-T is Benign according to our data. Variant chr19-8369216-C-T is described in ClinVar as [Benign]. Clinvar id is 783819.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1772/152248) while in subpopulation AFR AF = 0.0415 (1724/41554). AF 95% confidence interval is 0.0399. There are 35 homozygotes in GnomAd4. There are 859 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPTL4	NM_139314.3	c.548-3C>T		splice_region_variant, intron_variant	Intron 3 of 6	ENST00000301455.7	NP_647475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPTL4	ENST00000301455.7	c.548-3C>T		splice_region_variant, intron_variant	Intron 3 of 6	1	NM_139314.3	ENSP00000301455.1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1772 AN: 152130 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00288 AC: 704 AN: 244060 AF XY: 0.00228

Gnomad AFR exome AF: 0.0417

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000453

Gnomad OTH exome AF: 0.000511

GnomAD4 exome AF: 0.00111 AC: 1620 AN: 1456502 Hom.: 46 Cov.: 31 AF XY: 0.000994 AC XY: 720 AN XY: 724094

African (AFR) AF: 0.0438 AC: 1462 AN: 33388

American (AMR) AF: 0.00124 AC: 55 AN: 44230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25812

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 84852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.000893 AC: 4 AN: 4480

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1110730

Other (OTH) AF: 0.00140 AC: 84 AN: 60124

GnomAD4 genome AF: 0.0116 AC: 1772 AN: 152248 Hom.: 35 Cov.: 32 AF XY: 0.0115 AC XY: 859 AN XY: 74438

African (AFR) AF: 0.0415 AC: 1724 AN: 41554

American (AMR) AF: 0.00203 AC: 31 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00523 Hom.: 6

Bravo AF: 0.0126

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.5
DANN	Benign	0.77
PhyloP100		2.2
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.012
dbscSNV1_RF	Benign	0.23
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

Other links and lift over

dbSNP: rs34600793; hg19: chr19-8434100;