rs12287066

Variant names:

• chr11-116791615-G-T
• rs12287066
• NM_001371904.1:c.132C>A

Variant summary

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

The NM_001371904.1(APOA5):​c.132C>A​(p.Ile44Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0696 in 1,607,526 control chromosomes in the GnomAD database, including 4,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (981 hom., cov: 34)
  • Exomes 𝑓: 0.067 (3833 hom.)
• Consequence: APOA5 NM_001371904.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0250
• Publications: 25 publications found

Genes affected

APOA5 (HGNC:17288): (apolipoprotein A5) The protein encoded by this gene is an apolipoprotein that plays an important role in regulating the plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of high density lipoprotein and is highly similar to a rat protein that is upregulated in response to liver injury. Mutations in this gene have been associated with hypertriglyceridemia and hyperlipoproteinemia type 5. This gene is located proximal to the apolipoprotein gene cluster on chromosome 11q23. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Oct 2009]

APOA5 Gene-Disease associations (from GenCC):

• hypertriglyceridemia 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hyperlipoproteinemia type V

  Inheritance: AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 11-116791615-G-T is Benign according to our data. Variant chr11-116791615-G-T is described in ClinVar as Benign. ClinVar VariationId is 496495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA5	NM_001371904.1	c.132C>A	p.Ile44Ile	synonymous_variant	Exon 2 of 3	ENST00000227665.9	NP_001358833.1
APOA5	NM_001166598.2	c.132C>A	p.Ile44Ile	synonymous_variant	Exon 3 of 4		NP_001160070.1
APOA5	NM_052968.5	c.132C>A	p.Ile44Ile	synonymous_variant	Exon 3 of 4		NP_443200.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOA5	ENST00000227665.9	c.132C>A	p.Ile44Ile	synonymous_variant	Exon 2 of 3	1	NM_001371904.1	ENSP00000227665.4
APOA5	ENST00000433069.2	c.132C>A	p.Ile44Ile	synonymous_variant	Exon 3 of 4	1		ENSP00000399701.2
APOA5	ENST00000673688.1	c.132C>A	p.Ile44Ile	synonymous_variant	Exon 2 of 3			ENSP00000501141.1
APOA5	ENST00000542499.5	c.132C>A	p.Ile44Ile	synonymous_variant	Exon 3 of 4	5		ENSP00000445002.1

Frequencies

GnomAD3 genomes AF: 0.0986 AC: 14997 AN: 152162 Hom.: 976 Cov.: 34

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0741

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0416

Gnomad FIN AF: 0.0554

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0644

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.0773 AC: 18496 AN: 239316 AF XY: 0.0713

Gnomad AFR exome AF: 0.176

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.0738

Gnomad EAS exome AF: 0.000282

Gnomad FIN exome AF: 0.0606

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.0758

GnomAD4 exome AF: 0.0665 AC: 96790 AN: 1455246 Hom.: 3833 Cov.: 33 AF XY: 0.0650 AC XY: 46983 AN XY: 723326

African (AFR) AF: 0.179 AC: 5952 AN: 33296

American (AMR) AF: 0.153 AC: 6732 AN: 43930

Ashkenazi Jewish (ASJ) AF: 0.0710 AC: 1849 AN: 26024

East Asian (EAS) AF: 0.000559 AC: 22 AN: 39330

South Asian (SAS) AF: 0.0401 AC: 3416 AN: 85088

European-Finnish (FIN) AF: 0.0628 AC: 3313 AN: 52778

Middle Eastern (MID) AF: 0.0871 AC: 488 AN: 5602

European-Non Finnish (NFE) AF: 0.0639 AC: 70899 AN: 1109082

Other (OTH) AF: 0.0685 AC: 4119 AN: 60116

GnomAD4 genome AF: 0.0986 AC: 15020 AN: 152280 Hom.: 981 Cov.: 34 AF XY: 0.0973 AC XY: 7248 AN XY: 74478

African (AFR) AF: 0.175 AC: 7258 AN: 41546

American (AMR) AF: 0.129 AC: 1968 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0741 AC: 257 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0418 AC: 202 AN: 4828

European-Finnish (FIN) AF: 0.0554 AC: 588 AN: 10618

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0644 AC: 4380 AN: 68030

Other (OTH) AF: 0.104 AC: 220 AN: 2116

Alfa AF: 0.0896 Hom.: 567

Bravo AF: 0.109

Asia WGS AF: 0.0370 AC: 128 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Jul 19, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The APOA5 c.132C>A (p.Ile44Ile) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of SRp40. However, these predictions have yet to be confirmed by functional studies. This variant was found in 8225/74964 control chromosomes (443 homozygotes) from ExAC at a frequency of 0.1097193, which is approximately 1646 times the estimated maximal expected allele frequency of a pathogenic APOA5 variant (0.0000667), thus this variant is a common benign polymorphism. Taken together, this variant is classified as benign. -

Oct 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiovascular phenotype Benign:1

Feb 11, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.7
DANN	Benign	0.72
PhyloP100		-0.025
PromoterAI		0.022	Neutral
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: rs12287066; hg19: chr11-116662331; COSMIC: COSV57064511; COSMIC: COSV57064511;