rs2075291

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001371904.1(APOA5):c.553G>T(p.Gly185Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,612,572 control chromosomes in the GnomAD database, including 142 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G185D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0034 ( 13 hom., cov: 34)

Exomes 𝑓: 0.0029 ( 129 hom. )

Consequence

APOA5
NM_001371904.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4O:1

Conservation

PhyloP100: 0.159

Publications

184 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056571066).

BP6

Variant 11-116790676-C-A is Benign according to our data. Variant chr11-116790676-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4402.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
APOA5	NM_001371904.1 link	c.553G>T	p.Gly185Cys	missense_variant	Exon 3 of 3	ENST00000227665.9	NP_001358833.1
APOA5	NM_001166598.2 link	c.553G>T	p.Gly185Cys	missense_variant	Exon 4 of 4		NP_001160070.1
APOA5	NM_052968.5 link	c.553G>T	p.Gly185Cys	missense_variant	Exon 4 of 4		NP_443200.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
APOA5	ENST00000227665.9 link	c.553G>T	p.Gly185Cys	missense_variant	Exon 3 of 3	1	NM_001371904.1	ENSP00000227665.4
APOA5	ENST00000433069.2 link	c.553G>T	p.Gly185Cys	missense_variant	Exon 4 of 4	1		ENSP00000399701.2
APOA5	ENST00000673688.1 link	c.637G>T	p.Gly213Cys	missense_variant	Exon 3 of 3			ENSP00000501141.1
APOA5	ENST00000542499.5 link	c.553G>T	p.Gly185Cys	missense_variant	Exon 4 of 4	5		ENSP00000445002.1

Frequencies

GnomAD3 genomes

AF:

0.00342

AC:

521

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0661

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00637

AC:

1578

AN:

247782

AF XY:

0.00627

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0667

Gnomad FIN exome

AF:

0.000332

Gnomad NFE exome

AF:

0.000332

Gnomad OTH exome

AF:

0.00231

GnomAD4 exome

AF:

0.00286

AC:

4182

AN:

1460262

Hom.:

129

Cov.:

AF XY:

0.00314

AC XY:

2284

AN XY:

726492

show subpopulations

African (AFR)

AF:

0.00215

AC:

AN:

33474

American (AMR)

AF:

0.000335

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.0712

AC:

2825

AN:

39692

South Asian (SAS)

AF:

0.00902

AC:

778

AN:

86238

European-Finnish (FIN)

AF:

0.000327

AC:

AN:

52054

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000233

AC:

259

AN:

1111848

Other (OTH)

AF:

0.00335

AC:

202

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

323

646

969

1292

1615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.00341

AC:

520

AN:

152310

Hom.:

Cov.:

AF XY:

0.00431

AC XY:

321

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

41578

American (AMR)

AF:

0.000457

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0663

AC:

342

AN:

5162

South Asian (SAS)

AF:

0.0106

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68016

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

119

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:

0.00207

Hom.:

Bravo

AF:

0.00364

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.00613

AC:

744

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertriglyceridemia 1

Uncertain:1Other:1

Oct 01, 2003

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27813673, 31901151, 31619059, 30132804, 30420299, 29263402, 28548292, 27516387, 26079787, 26690388, 25843152, 12915450, 21423763, 20134407, 25487149, 22008704, 25127531, 18635818) -

not specified

Benign:1

Mar 05, 2024

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: APOA5 c.553G>T (p.Gly185Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0064 in 248436 control chromosomes, predominantly at a frequency of 0.067 within the East Asian subpopulation in the gnomAD database, including 54 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1005 fold of the estimated maximal expected allele frequency for a pathogenic variant in APOA5 causing Hypertriglyceridemia phenotype (6.7e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The following publications have been ascertained in the context of this evaluation (PMID: 18635818, 25127531, 20657596). ClinVar contains an entry for this variant (Variation ID: 4402). Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiovascular phenotype

Benign:1

May 24, 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

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;D

Eigen

Benign

0.011

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.73

.;T

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.4

M;M

PhyloP100

0.16

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.4

D;D

REVEL

Benign

0.28

Sift

Uncertain

0.021

D;D

Sift4G

Uncertain

0.010

D;D

Polyphen

1.0

D;D

Vest4

0.33

MVP

0.91

MPC

1.4

ClinPred

0.019

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.40

gMVP

0.49

Mutation Taster

=94/6

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over