rs4225

Variant names:

• chr11-116832955-G-T
• rs4225
• NM_000040.3:c.*71G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000040.3(APOC3):​c.*71G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,606,286 control chromosomes in the GnomAD database, including 274,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (18615 hom., cov: 33)
  • Exomes 𝑓: 0.58 (256337 hom.)
• Consequence: APOC3 NM_000040.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.142
• Publications: 34 publications found

Genes affected

APOC3 (HGNC:610): (apolipoprotein C3) This gene encodes a protein component of triglyceride (TG)-rich lipoproteins (TRLs) including very low density lipoproteins (VLDL), high density lipoproteins (HDL) and chylomicrons. The encoded protein plays a role in role in the metabolism of these TRLs through multiple modes. This protein has been shown to promote the secretion of VLDL1, inhibit lipoprotein lipase enzyme activity, and delay catabolism of TRL remnants. Mutations in this gene are associated with low plasma triglyceride levels and reduced risk of ischemic cardiovascular disease, and hyperalphalipoproteinemia, which is characterized by elevated levels of high density lipoprotein (HDL) and HDL cholesterol in human patients. This gene and other related genes comprise an apolipoprotein gene cluster on chromosome 11. [provided by RefSeq, Sep 2017]

APOC3 Gene-Disease associations (from GenCC):

• cholesterol-ester transfer protein deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-116832955-G-T is Benign according to our data. Variant chr11-116832955-G-T is described in ClinVar as Benign. ClinVar VariationId is 1225805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOC3	NM_000040.3	c.*71G>T		3_prime_UTR_variant	Exon 4 of 4	ENST00000227667.8	NP_000031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOC3	ENST00000227667.8	c.*71G>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_000040.3	ENSP00000227667.2
APOC3	ENST00000630701.1	c.*71G>T		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000486182.1
APOC3	ENST00000375345.3	c.*71G>T		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000364494.1

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68199 AN: 151968 Hom.: 18618 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.788

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.477

GnomAD4 exome AF: 0.579 AC: 841593 AN: 1454200 Hom.: 256337 Cov.: 30 AF XY: 0.572 AC XY: 414102 AN XY: 723704

African (AFR) AF: 0.136 AC: 4531 AN: 33270

American (AMR) AF: 0.432 AC: 19239 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 14091 AN: 26090

East Asian (EAS) AF: 0.176 AC: 6969 AN: 39636

South Asian (SAS) AF: 0.318 AC: 27333 AN: 85896

European-Finnish (FIN) AF: 0.544 AC: 28459 AN: 52324

Middle Eastern (MID) AF: 0.486 AC: 2386 AN: 4908

European-Non Finnish (NFE) AF: 0.638 AC: 706178 AN: 1107454

Other (OTH) AF: 0.540 AC: 32407 AN: 60062

GnomAD4 genome AF: 0.448 AC: 68184 AN: 152086 Hom.: 18615 Cov.: 33 AF XY: 0.440 AC XY: 32704 AN XY: 74326

African (AFR) AF: 0.158 AC: 6568 AN: 41522

American (AMR) AF: 0.463 AC: 7083 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1889 AN: 3466

East Asian (EAS) AF: 0.203 AC: 1046 AN: 5162

South Asian (SAS) AF: 0.300 AC: 1445 AN: 4818

European-Finnish (FIN) AF: 0.540 AC: 5692 AN: 10550

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.627 AC: 42605 AN: 67960

Other (OTH) AF: 0.471 AC: 992 AN: 2108

Alfa AF: 0.479 Hom.: 2945

Bravo AF: 0.433

Asia WGS AF: 0.215 AC: 752 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30420299, 30782561, 27624799) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.2
DANN	Benign	0.76
PhyloP100		-0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs4225; hg19: chr11-116703671; COSMIC: COSV52635690; COSMIC: COSV52635690;