11-116791691-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001371904.1(APOA5):c.56C>G(p.Ser19Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0624 in 1,607,778 control chromosomes in the GnomAD database, including 3,555 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S19L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.065 ( 352 hom., cov: 34)

Exomes 𝑓: 0.062 ( 3203 hom. )

Consequence

APOA5
NM_001371904.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 1.58

Publications

365 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=0.0018840134).

BP6

Variant 11-116791691-G-C is Benign according to our data. Variant chr11-116791691-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 4403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371904.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
APOA5	NM_001371904.1	MANE Select	c.56C>G	p.Ser19Trp	missense	Exon 2 of 3	NP_001358833.1
APOA5	NM_001166598.2		c.56C>G	p.Ser19Trp	missense	Exon 3 of 4	NP_001160070.1
APOA5	NM_052968.5		c.56C>G	p.Ser19Trp	missense	Exon 3 of 4	NP_443200.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
APOA5	ENST00000227665.9	TSL:1 MANE Select	c.56C>G	p.Ser19Trp	missense	Exon 2 of 3	ENSP00000227665.4
APOA5	ENST00000433069.2	TSL:1	c.56C>G	p.Ser19Trp	missense	Exon 3 of 4	ENSP00000399701.2
APOA5	ENST00000673688.1		c.56C>G	p.Ser19Trp	missense	Exon 2 of 3	ENSP00000501141.1

Frequencies

GnomAD3 genomes

AF:

0.0649

AC:

9872

AN:

152200

Hom.:

349

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0619

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.113

Gnomad ASJ

AF:

0.0657

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0405

Gnomad FIN

AF:

0.0551

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0628

Gnomad OTH

AF:

0.0779

GnomAD2 exomes

AF:

0.0684

AC:

16228

AN:

237114

AF XY:

0.0645

show subpopulations

Gnomad AFR exome

AF:

0.0635

Gnomad AMR exome

AF:

0.153

Gnomad ASJ exome

AF:

0.0681

Gnomad EAS exome

AF:

0.000286

Gnomad FIN exome

AF:

0.0608

Gnomad NFE exome

AF:

0.0640

Gnomad OTH exome

AF:

0.0701

GnomAD4 exome

AF:

0.0621

AC:

90359

AN:

1455460

Hom.:

3203

Cov.:

AF XY:

0.0610

AC XY:

44118

AN XY:

723514

show subpopulations

African (AFR)

AF:

0.0645

AC:

2148

AN:

33286

American (AMR)

AF:

0.147

AC:

6413

AN:

43700

Ashkenazi Jewish (ASJ)

AF:

0.0653

AC:

1697

AN:

25982

East Asian (EAS)

AF:

0.000559

AC:

AN:

39364

South Asian (SAS)

AF:

0.0387

AC:

3297

AN:

85286

European-Finnish (FIN)

AF:

0.0626

AC:

3319

AN:

52982

Middle Eastern (MID)

AF:

0.0542

AC:

312

AN:

5760

European-Non Finnish (NFE)

AF:

0.0627

AC:

69507

AN:

1108956

Other (OTH)

AF:

0.0606

AC:

3644

AN:

60144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

5272

10543

15815

21086

26358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2602

5204

7806

10408

13010

<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:

0.0649

AC:

9890

AN:

152318

Hom.:

352

Cov.:

AF XY:

0.0642

AC XY:

4778

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0619

AC:

2574

AN:

41574

American (AMR)

AF:

0.114

AC:

1737

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0657

AC:

228

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0408

AC:

197

AN:

4832

European-Finnish (FIN)

AF:

0.0551

AC:

585

AN:

10616

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0628

AC:

4275

AN:

68026

Other (OTH)

AF:

0.0776

AC:

164

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

494

987

1481

1974

2468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0542

Hom.:

191

Bravo

AF:

0.0704

TwinsUK

AF:

0.0620

AC:

230

ALSPAC

AF:

0.0643

AC:

248

ESP6500AA

AF:

0.0611

AC:

269

ESP6500EA

AF:

0.0649

AC:

558

ExAC

AF:

0.0620

AC:

7527

Asia WGS

AF:

0.0300

AC:

104

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jul 18, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

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

Familial type 5 hyperlipoproteinemia;C5444012:Hypertriglyceridemia 1

Benign:1

Apr 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Hypertriglyceridemia 1

Other:1

Nov 15, 2002

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.84

MutationAssessor

Benign

2.0

PhyloP100

1.6

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.9

REVEL

Benign

0.22

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.43

MPC

1.5

ClinPred

0.017

GERP RS

5.4

PromoterAI

-0.0094

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.098

gMVP

0.42

Mutation Taster

=99/1

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over