11-116820918-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/18 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:2
• Conservation: PhyloP100: -0.513

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOA4	NM_000482.4	c.1140G>T	p.Gln380His	missense_variant	3/3	ENST00000357780.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOA4	ENST00000357780.5	c.1140G>T	p.Gln380His	missense_variant	3/3	1	NM_000482.4	P1
	ENST00000645414.1	n.169-102C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0519 AC: 7905 AN: 152210 Hom.: 306 Cov.: 33

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

GnomAD3 exomes AF: 0.0523 AC: 13128 AN: 251086 Hom.: 470 AF XY: 0.0528 AC XY: 7162 AN XY: 135722

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 SAS exome AF: 0.0188

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.: 67 AF XY: 0.0730 AC XY: 53054 AN XY: 727142

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.0383

Gnomad4 ASJ exome AF: 0.0665

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0192

Gnomad4 FIN exome AF: 0.0513

Gnomad4 NFE exome AF: 0.0878

Gnomad4 OTH exome AF: 0.0651

GnomAD4 genome AF: 0.0519 AC: 7904 AN: 152328 Hom.: 306 Cov.: 33 AF XY: 0.0483 AC XY: 3600 AN XY: 74480

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.0500

Gnomad4 ASJ AF: 0.0628

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.0488

Gnomad4 NFE AF: 0.0809

Gnomad4 OTH AF: 0.0510

Alfa AF: 0.0701 Hom.: 920

Bravo AF: 0.0523

TwinsUK AF: 0.0876 AC: 325

ALSPAC AF: 0.0944 AC: 364

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.0829 AC: 712

ExAC AF: 0.0524 AC: 6357

Asia WGS AF: 0.00779 AC: 30 AN: 3478

EpiCase AF: 0.0775

EpiControl AF: 0.0772

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 9714133, 20117098, 1349197) -

APOLIPOPROTEIN A-IV POLYMORPHISM, APOA4*1/APOA4*2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	0.24
Dann	Benign	0.58
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.017	N
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.047
Sift	Benign	0.45	T
Sift4G	Benign	0.19	T
Vest4		0.051
MutPred		0.25		Loss of solvent accessibility (P = 0.0635);
MPC		0.050
ClinPred		0.00085	T
GERP RS		0.14
gMVP		0.20

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

Other links and lift over

dbSNP: rs5110; hg19: chr11-116691634; COSMIC: COSV63361267;