rs5104

Variant names:

• chr11-116821618-C-T
• rs5104
• NM_000482.4:c.440G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-116821618-C-T
• chr11-116821618-C-A
• chr11-116821618-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000482.4(APOA4):​c.440G>A​(p.Ser147Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.848 in 1,610,506 control chromosomes in the GnomAD database, including 582,863 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54195 hom., cov: 35)
  • Exomes 𝑓: 0.85 (528668 hom.)
• Consequence: APOA4 NM_000482.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.23
• Publications: 68 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]

APOA4 Gene-Disease associations (from GenCC):

• autosomal dominant medullary cystic kidney disease with or without hyperuricemia

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000305923 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.884688E-7).
• BP6: Variant 11-116821618-C-T is Benign according to our data. Variant chr11-116821618-C-T is described in ClinVar as Benign. ClinVar VariationId is 1268136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOA4	NM_000482.4	MANE Select	c.440G>A	p.Ser147Asn	missense	Exon 3 of 3	NP_000473.2	P06727

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOA4	ENST00000357780.5	TSL:1 MANE Select	c.440G>A	p.Ser147Asn	missense	Exon 3 of 3	ENSP00000350425.3	P06727
	ENSG00000305923	ENST00000814126.1		n.136-6547C>T		intron	N/A
	ENSG00000285513	ENST00000645414.1		n.*77C>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.841 AC: 127939 AN: 152144 Hom.: 54162 Cov.: 35

Gnomad AFR AF: 0.885

Gnomad AMI AF: 0.944

Gnomad AMR AF: 0.771

Gnomad ASJ AF: 0.802

Gnomad EAS AF: 0.667

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.760

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.869

Gnomad OTH AF: 0.833

GnomAD2 exomes AF: 0.804 AC: 198432 AN: 246798 AF XY: 0.800

Gnomad AFR exome AF: 0.886

Gnomad AMR exome AF: 0.758

Gnomad ASJ exome AF: 0.802

Gnomad EAS exome AF: 0.674

Gnomad FIN exome AF: 0.769

Gnomad NFE exome AF: 0.869

Gnomad OTH exome AF: 0.819

GnomAD4 exome AF: 0.849 AC: 1237727 AN: 1458244 Hom.: 528668 Cov.: 60 AF XY: 0.843 AC XY: 611456 AN XY: 725340

African (AFR) AF: 0.888 AC: 29696 AN: 33438

American (AMR) AF: 0.760 AC: 33894 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.799 AC: 20830 AN: 26064

East Asian (EAS) AF: 0.655 AC: 25994 AN: 39658

South Asian (SAS) AF: 0.676 AC: 58271 AN: 86170

European-Finnish (FIN) AF: 0.772 AC: 39665 AN: 51376

Middle Eastern (MID) AF: 0.835 AC: 4808 AN: 5758

European-Non Finnish (NFE) AF: 0.877 AC: 974141 AN: 1110870

Other (OTH) AF: 0.836 AC: 50428 AN: 60316

GnomAD4 genome AF: 0.841 AC: 128028 AN: 152262 Hom.: 54195 Cov.: 35 AF XY: 0.830 AC XY: 61749 AN XY: 74432

African (AFR) AF: 0.885 AC: 36811 AN: 41576

American (AMR) AF: 0.771 AC: 11788 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 2784 AN: 3472

East Asian (EAS) AF: 0.668 AC: 3443 AN: 5158

South Asian (SAS) AF: 0.659 AC: 3184 AN: 4830

European-Finnish (FIN) AF: 0.760 AC: 8054 AN: 10602

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.869 AC: 59104 AN: 68018

Other (OTH) AF: 0.829 AC: 1751 AN: 2112

Alfa AF: 0.856 Hom.: 83542

Bravo AF: 0.850

TwinsUK AF: 0.879 AC: 3260

ALSPAC AF: 0.877 AC: 3381

ESP6500AA AF: 0.881 AC: 3877

ESP6500EA AF: 0.870 AC: 7476

ExAC AF: 0.807 AC: 97779

Asia WGS AF: 0.675 AC: 2350 AN: 3478

EpiCase AF: 0.866

EpiControl AF: 0.869

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.023
DANN	Benign	0.21
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0049	N
MetaRNN	Benign	8.9e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.2
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.87	N
REVEL	Benign	0.042
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.014
MPC		0.049
ClinPred		0.014	T
GERP RS		-7.0
gMVP		0.22
Mutation Taster		=98/2	polymorphism (auto)

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: rs5104; hg19: chr11-116692334; COSMIC: COSV63360210; COSMIC: COSV63360210;