11-116791636-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001371904.1(APOA5):c.111C>A(p.Asp37Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,610,130 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 29 hom., cov: 34)

Exomes 𝑓: 0.0012 ( 20 hom. )

Consequence

APOA5
NM_001371904.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.673

Publications

12 publications found

Variant links:

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

APOA5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0041744113).

BP6

Variant 11-116791636-G-T is Benign according to our data. Variant chr11-116791636-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 496494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1597/152350) while in subpopulation AFR AF = 0.0368 (1528/41578). AF 95% confidence interval is 0.0352. There are 29 homozygotes in GnomAd4. There are 743 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 1597 AD,SD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
APOA5	NM_001371904.1 link	c.111C>A	p.Asp37Glu	missense_variant	Exon 2 of 3	ENST00000227665.9	NP_001358833.1
APOA5	NM_001166598.2 link	c.111C>A	p.Asp37Glu	missense_variant	Exon 3 of 4		NP_001160070.1
APOA5	NM_052968.5 link	c.111C>A	p.Asp37Glu	missense_variant	Exon 3 of 4		NP_443200.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
APOA5	ENST00000227665.9 link	c.111C>A	p.Asp37Glu	missense_variant	Exon 2 of 3	1	NM_001371904.1	ENSP00000227665.4
APOA5	ENST00000433069.2 link	c.111C>A	p.Asp37Glu	missense_variant	Exon 3 of 4	1		ENSP00000399701.2
APOA5	ENST00000673688.1 link	c.111C>A	p.Asp37Glu	missense_variant	Exon 2 of 3			ENSP00000501141.1
APOA5	ENST00000542499.5 link	c.111C>A	p.Asp37Glu	missense_variant	Exon 3 of 4	5		ENSP00000445002.1

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1595

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0368

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00282

AC:

682

AN:

242240

AF XY:

0.00202

show subpopulations

Gnomad AFR exome

AF:

0.0362

Gnomad AMR exome

AF:

0.00204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000422

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.00125

AC:

1816

AN:

1457780

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

806

AN XY:

724818

show subpopulations

African (AFR)

AF:

0.0369

AC:

1230

AN:

33360

American (AMR)

AF:

0.00260

AC:

115

AN:

44292

Ashkenazi Jewish (ASJ)

AF:

0.0000768

AC:

AN:

26046

East Asian (EAS)

AF:

0.00

AC:

AN:

39484

South Asian (SAS)

AF:

0.0000702

AC:

AN:

85432

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

53030

Middle Eastern (MID)

AF:

0.00227

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.000254

AC:

282

AN:

1110186

Other (OTH)

AF:

0.00277

AC:

167

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

119

239

358

478

597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0105

AC:

1597

AN:

152350

Hom.:

Cov.:

AF XY:

0.00997

AC XY:

743

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0368

AC:

1528

AN:

41578

American (AMR)

AF:

0.00222

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

68032

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

159

239

318

398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00393

Hom.:

Bravo

AF:

0.0110

ESP6500AA

AF:

0.0330

AC:

145

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.00325

AC:

394

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 28, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jul 21, 2017

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The APOA5 c.111C>A (p.Asp37Glu) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 377/95056 control chromosomes (7 homozygotes) including ExAC, predominantly observed in the African subpopulation at a frequency of 0.042891 (330/7694). This frequency is about 643 times the estimated maximal expected allele frequency of a pathogenic APOA5 variant (0.0000667), thus this is a polymorphism found primarily in the populations of African origin. A case-control study indicates that the variants prevalence is increased in myocardial infarction cases than in controls (Do_2015). No further studies are found to replicate this finding. Taken together, this variant is currently classified as likely benign.

Cardiovascular phenotype

Benign:1

Feb 05, 2021

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

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.28

T;T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.0

.;T;T

MetaRNN

Benign

0.0042

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.4

L;L;.

PhyloP100

0.67

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.71

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.41

T;T;T

Vest4

0.10

ClinPred

0.0010

GERP RS

1.2

PromoterAI

-0.073

Neutral

(source)

Varity_R

0.048

gMVP

0.50

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over