11-116820959-T-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.1099A>T(p.Thr367Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,613,684 control chromosomes in the GnomAD database, including 27,179 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T367A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2071 hom., cov: 33)
  • Exomes 𝑓: 0.18 (25108 hom.)
• Consequence: APOA4 NM_000482.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.211

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=0.001034677).
• BP6: Variant 11-116820959-T-A is Benign according to our data. Variant chr11-116820959-T-A is described in ClinVar as [Benign]. Clinvar id is 1245704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOA4	NM_000482.4	c.1099A>T	p.Thr367Ser	missense_variant	3/3	ENST00000357780.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOA4	ENST00000357780.5	c.1099A>T	p.Thr367Ser	missense_variant	3/3	1	NM_000482.4	P1
	ENST00000645414.1	n.169-61T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23864 AN: 151724 Hom.: 2072 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.168

GnomAD3 exomes AF: 0.150 AC: 37745 AN: 251308 Hom.: 3213 AF XY: 0.155 AC XY: 21101 AN XY: 135836

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.0941

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.000652

Gnomad SAS exome AF: 0.129

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.180 AC: 262873 AN: 1461840 Hom.: 25108 Cov.: 78 AF XY: 0.180 AC XY: 130631 AN XY: 727224

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.100

Gnomad4 ASJ exome AF: 0.213

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.134

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.196

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.157 AC: 23881 AN: 151844 Hom.: 2071 Cov.: 33 AF XY: 0.154 AC XY: 11402 AN XY: 74192

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.201

Gnomad4 OTH AF: 0.165

Alfa AF: 0.169 Hom.: 1478

Bravo AF: 0.154

TwinsUK AF: 0.201 AC: 745

ALSPAC AF: 0.201 AC: 775

ESP6500AA AF: 0.113 AC: 496

ESP6500EA AF: 0.197 AC: 1693

ExAC AF: 0.150 AC: 18255

EpiCase AF: 0.201

EpiControl AF: 0.202

ClinVar

Significance: Benign

Submissions summary: 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 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 1349197, 23096082, 12676816, 20117098) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	5.6
Dann	Benign	0.40
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
MetaRNN	Benign	0.0010	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.023
Sift	Benign	0.50	T
Sift4G	Benign	0.79	T
Vest4		0.022
MutPred		0.13		Loss of methylation at K366 (P = 0.1326);
MPC		0.049
ClinPred		0.00030	T
GERP RS		0.012
gMVP		0.086

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: rs675; hg19: chr11-116691675; COSMIC: COSV63360269;