Genetic Variant NM_000482.4:c.1140G>T (chr11-116820918-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_000482.4(APOA4):c.1140G>T(p.Gln380His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.073 in 1,614,064 control chromosomes in the GnomAD database, including 4,952 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.052 ( 306 hom., cov: 33)

Exomes 𝑓: 0.075 ( 4646 hom. )

Consequence

APOA4
NM_000482.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:3

Conservation

PhyloP100: -0.513

Publications

59 publications found

Variant links:

Genes affected

APOA4 (HGNC:602): (apolipoprotein A4) Apoliprotein (apo) A-IV gene contains 3 exons separated by two introns. A sequence polymorphism has been identified in the 3'UTR of the third exon. The primary translation product is a 396-residue preprotein which after proteolytic processing is secreted its primary site of synthesis, the intestine, in association with chylomicron particles. Although its precise function is not known, apo A-IV is a potent activator of lecithin-cholesterol acyltransferase in vitro. [provided by RefSeq, Jul 2008]

APOA4 Gene-Disease associations (from GenCC):

autosomal dominant medullary cystic kidney disease with or without hyperuricemia
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

APOA4 links:

ENSG00000285513 (HGNC:):

ENSG00000285513 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=0.0017547011).

BP6

Variant 11-116820918-C-A is Benign according to our data. Variant chr11-116820918-C-A is described in ClinVar as Benign. ClinVar VariationId is 17905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0791 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000482.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOA4	NM_000482.4	MANE Select	c.1140G>T	p.Gln380His	missense	Exon 3 of 3	NP_000473.2	P06727

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOA4	ENST00000357780.5	TSL:1 MANE Select	c.1140G>T	p.Gln380His	missense	Exon 3 of 3	ENSP00000350425.3	P06727
ENSG00000285513	ENST00000645414.1		n.169-102C>A		intron	N/A
ENSG00000305923	ENST00000814126.1		n.135+6578C>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0519

AC:

7905

AN:

152210

Hom.:

306

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.0500

Gnomad ASJ

AF:

0.0628

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.0488

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0809

Gnomad OTH

AF:

0.0516

GnomAD2 exomes

AF:

0.0523

AC:

13128

AN:

251086

AF XY:

0.0528

show subpopulations

Gnomad AFR exome

AF:

0.0143

Gnomad AMR exome

AF:

0.0361

Gnomad ASJ exome

AF:

0.0665

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0516

Gnomad NFE exome

AF:

0.0784

Gnomad OTH exome

AF:

0.0636

GnomAD4 exome

AF:

0.0752

AC:

109875

AN:

1461736

Hom.:

4646

Cov.:

AF XY:

0.0730

AC XY:

53054

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.0119

AC:

398

AN:

33480

American (AMR)

AF:

0.0383

AC:

1712

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0665

AC:

1738

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0192

AC:

1655

AN:

86252

European-Finnish (FIN)

AF:

0.0513

AC:

2741

AN:

53404

Middle Eastern (MID)

AF:

0.0201

AC:

116

AN:

5768

European-Non Finnish (NFE)

AF:

0.0878

AC:

97576

AN:

1111900

Other (OTH)

AF:

0.0651

AC:

3933

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

6224

12447

18671

24894

31118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3582

7164

10746

14328

17910

<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:

0.0519

AC:

7904

AN:

152328

Hom.:

306

Cov.:

AF XY:

0.0483

AC XY:

3600

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0155

AC:

645

AN:

41578

American (AMR)

AF:

0.0500

AC:

766

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0628

AC:

218

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0170

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0488

AC:

518

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0809

AC:

5504

AN:

68012

Other (OTH)

AF:

0.0510

AC:

108

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

359

718

1077

1436

1795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0681

Hom.:

1287

Bravo

AF:

0.0523

TwinsUK

AF:

0.0876

AC:

325

ALSPAC

AF:

0.0944

AC:

364

ESP6500AA

AF:

0.0177

AC:

ESP6500EA

AF:

0.0829

AC:

712

ExAC

AF:

0.0524

AC:

6357

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0775

EpiControl

AF:

0.0772

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

APOLIPOPROTEIN A-IV POLYMORPHISM, APOA4*1/APOA4*2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.24

(source)

DANN

Benign

0.58

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.017

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

PhyloP100

-0.51

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.17

REVEL

Benign

0.047

Sift

Benign

0.45

Sift4G

Benign

0.19

Vest4

0.051

MutPred

0.25

Loss of solvent accessibility (P = 0.0635)

MPC

0.050

ClinPred

0.00085

GERP RS

0.14

gMVP

0.20

Mutation Taster

=98/2

disease causing (ClinVar)

(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

Computational scores

Splicing

Publications

Other links and lift over