11-116790267-T-A

Position:

chr11-116790267-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001371904.1(APOA5):c.962A>T(p.His321Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000575 in 1,614,244 control chromosomes in the GnomAD database, including 3 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 (★★).

Frequency

Genomes: 𝑓 0.00070 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00056 ( 2 hom. )

Consequence

APOA5
NM_001371904.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.44

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009387463).

BP6

Variant 11-116790267-T-A is Benign according to our data. Variant chr11-116790267-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 496500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-116790267-T-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000696 (106/152350) while in subpopulation NFE AF= 0.000603 (41/68024). AF 95% confidence interval is 0.000457. There are 1 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
APOA5	NM_001371904.1 linkuse as main transcript	c.962A>T	p.His321Leu	missense_variant	3/3	ENST00000227665.9	NP_001358833.1
APOA5	NM_001166598.2 linkuse as main transcript	c.962A>T	p.His321Leu	missense_variant	4/4		NP_001160070.1
APOA5	NM_052968.5 linkuse as main transcript	c.962A>T	p.His321Leu	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.962A>T	p.His321Leu	missense_variant	3/3	1	NM_001371904.1	ENSP00000227665	P1
APOA5	ENST00000433069.2 linkuse as main transcript	c.962A>T	p.His321Leu	missense_variant	4/4	1		ENSP00000399701	P1
APOA5	ENST00000673688.1 linkuse as main transcript	c.1046A>T	p.His349Leu	missense_variant	3/3			ENSP00000501141
APOA5	ENST00000542499.5 linkuse as main transcript	c.962A>T	p.His321Leu	missense_variant	4/4	5		ENSP00000445002	P1

Frequencies

GnomAD3 genomes

AF:

0.000696

AC:

106

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00593

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000951

AC:

239

AN:

251368

Hom.:

AF XY:

0.000942

AC XY:

128

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00591

Gnomad NFE exome

AF:

0.000853

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000562

AC:

822

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000545

AC XY:

396

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00638

Gnomad4 NFE exome

AF:

0.000399

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.000696

AC:

106

AN:

152350

Hom.:

Cov.:

AF XY:

0.000913

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00593

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000314

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00110

AC:

133

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 17, 2017

Variant summary: The APOA5 c.962A>T (p.His321Leu) variant involves the alteration of a conserved nucleotide. 2/2 in silico tools predict damaging outcome for this variant (Mutation Taster and SNPs&GO not captured due to low reliability index). This variant was found in 133/121198 control chromosomes (1 homozygote) from ExAC at a frequency of 0.0010974, which is approximately 55 times the estimated maximal expected allele frequency of a pathogenic APOA5 variant (0.00002), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as benign. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

This alteration is classified as likely 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

-0.24

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.41

T;T

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.70

.;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.0094

T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

0.75

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.41

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.98

D;D

Vest4

0.56

MVP

0.93

MPC

1.6

ClinPred

0.073

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.45

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