rs2075291

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

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

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/exons	MANE	Protein
APOA5	NM_001371904.1 linkuse as main transcript	c.553G>T	p.Gly185Cys	missense_variant	3/3	ENST00000227665.9	NP_001358833.1
APOA5	NM_001166598.2 linkuse as main transcript	c.553G>T	p.Gly185Cys	missense_variant	4/4		NP_001160070.1
APOA5	NM_052968.5 linkuse as main transcript	c.553G>T	p.Gly185Cys	missense_variant	4/4		NP_443200.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
APOA5	ENST00000227665.9 linkuse as main transcript	c.553G>T	p.Gly185Cys	missense_variant	3/3	1	NM_001371904.1	ENSP00000227665	P1
APOA5	ENST00000433069.2 linkuse as main transcript	c.553G>T	p.Gly185Cys	missense_variant	4/4	1		ENSP00000399701	P1
APOA5	ENST00000673688.1 linkuse as main transcript	c.637G>T	p.Gly213Cys	missense_variant	3/3			ENSP00000501141
APOA5	ENST00000542499.5 linkuse as main transcript	c.553G>T	p.Gly185Cys	missense_variant	4/4	5		ENSP00000445002	P1

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

GnomAD3 exomes

AF:

0.00637

AC:

1578

AN:

247782

Hom.:

AF XY:

0.00627

AC XY:

844

AN XY:

134646

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 SAS exome

AF:

0.00841

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

Gnomad4 AFR exome

AF:

0.00215

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0712

Gnomad4 SAS exome

AF:

0.00902

Gnomad4 FIN exome

AF:

0.000327

Gnomad4 NFE exome

AF:

0.000233

Gnomad4 OTH exome

AF:

0.00335

GnomAD4 genome

AF:

0.00341

AC:

520

AN:

152310

Hom.:

Cov.:

AF XY:

0.00431

AC XY:

321

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00224

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0663

Gnomad4 SAS

AF:

0.0106

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00220

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

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
risk factor, no assertion criteria provided	literature only	OMIM	Oct 01, 2003	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2018	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) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 05, 2024

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2019

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

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

MutationTaster

Benign

1.0

N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over