11-116821310-C-G

Variant names:

• chr11-116821310-C-G
• rs121909576
• NM_000482.4:c.748G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000482.4(APOA4):​c.748G>C​(p.Glu250Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E250K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: APOA4 NM_000482.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 13 publications found

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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40657306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA4	NM_000482.4	c.748G>C	p.Glu250Gln	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.748G>C	p.Glu250Gln	missense_variant	Exon 3 of 3	1	NM_000482.4	ENSP00000350425.3
ENSG00000285513	ENST00000645414.1	n.459C>G		non_coding_transcript_exon_variant	Exon 2 of 2
ENSG00000305923	ENST00000814126.1	n.136-6855C>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461614 Hom.: 0 Cov.: 86 AF XY: 0.00 AC XY: 0 AN XY: 727136

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.67	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.18	D
PhyloP100		1.2
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.014	D
Sift4G	Benign	0.12	T
Vest4		0.22
MutPred		0.48		Gain of MoRF binding (P = 0.0218);
MVP		0.76
MPC		0.28
ClinPred		0.95	D
GERP RS		5.0
gMVP		0.31
Mutation Taster		=77/23	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

Other links and lift over

dbSNP: rs121909576; hg19: chr11-116692026;