11-116821052-C-T

Variant names:

• chr11-116821052-C-T
• rs145761354
• NM_000482.4:c.1006G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000482.4(APOA4):​c.1006G>A​(p.Val336Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,614,234 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V336V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00080 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: APOA4 NM_000482.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.71

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]

ENSG00000285513 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016444653).
• BP6: Variant 11-116821052-C-T is Benign according to our data. Variant chr11-116821052-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1524279.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA4	NM_000482.4	c.1006G>A	p.Val336Met	missense_variant	Exon 3 of 3	ENST00000357780.5	NP_000473.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOA4	ENST00000357780.5	c.1006G>A	p.Val336Met	missense_variant	Exon 3 of 3	1	NM_000482.4	ENSP00000350425.3
ENSG00000285513	ENST00000645414.1	n.201C>T		non_coding_transcript_exon_variant	Exon 2 of 2
ENSG00000305923	ENST00000814126.1	n.135+6712C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.000801 AC: 122 AN: 152248 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000628 AC: 158 AN: 251478 AF XY: 0.000655

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.00135 AC: 1980 AN: 1461868 Hom.: 3 Cov.: 86 AF XY: 0.00130 AC XY: 943 AN XY: 727236

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00167 AC: 1854 AN: 1112012

Other (OTH) AF: 0.00139 AC: 84 AN: 60396

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152366 Hom.: 1 Cov.: 33 AF XY: 0.000644 AC XY: 48 AN XY: 74508

African (AFR) AF: 0.000433 AC: 18 AN: 41586

American (AMR) AF: 0.000523 AC: 8 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00137 AC: 93 AN: 68044

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000948 Hom.: 1

Bravo AF: 0.000774

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000552 AC: 67

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APOA4: BP4 -

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 336 of the APOA4 protein (p.Val336Met). This variant is present in population databases (rs145761354, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dyslipidemia and/or low HDL cholesterol and coronary artery disease (PMID: 33130088, 36325899). ClinVar contains an entry for this variant (Variation ID: 1524279). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt APOA4 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on APOA4 function (PMID: 33130088). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.48
DANN	Benign	0.73
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.020	N
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.95	T
PhyloP100		-2.7
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.17
Sift	Benign	0.22	T
Sift4G	Benign	0.23	T
Vest4		0.071
MVP		0.36
MPC		0.059
ClinPred		0.0047	T
GERP RS		-3.1
gMVP		0.16
Mutation Taster		=95/5	polymorphism

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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Other links and lift over

dbSNP: rs145761354; hg19: chr11-116691768;