Genetic Variant APOA4:p.Glu250Gln (chr11-116821310-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.18

Publications

13 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 links:

ENSG00000285513 (HGNC:):

ENSG00000285513 links:

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ACMG classification

Classification was made for transcript

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).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOA4	NM_000482.4	MANE Select	c.748G>C	p.Glu250Gln	missense	Exon 3 of 3	NP_000473.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
APOA4	ENST00000357780.5	TSL:1 MANE Select	c.748G>C	p.Glu250Gln	missense	Exon 3 of 3	ENSP00000350425.3
ENSG00000285513	ENST00000645414.1		n.459C>G		non_coding_transcript_exon	Exon 2 of 2
ENSG00000305923	ENST00000814126.1		n.136-6855C>G		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461614

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111988

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.67

M_CAP

Benign

0.082

MetaRNN

Benign

0.41

MetaSVM

Uncertain

0.18

PhyloP100

1.2

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.43

Sift

Uncertain

0.014

Sift4G

Benign

0.12

Vest4

0.22

MutPred

0.48

Gain of MoRF binding (P = 0.0218)

MVP

0.76

MPC

0.28

ClinPred

0.95

GERP RS

5.0

gMVP

0.31

Mutation Taster

=77/23

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over