chr11-116821004-T-A

Variant names:

• chr11-116821004-T-A
• rs147577451
• NM_000482.4:c.1054A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000482.4(APOA4):​c.1054A>T​(p.Asn352Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,614,114 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: APOA4 NM_000482.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0470
• Publications: 5 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

ENSG00000285513 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048898757).

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.1054A>T	p.Asn352Tyr	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.1054A>T	p.Asn352Tyr	missense	Exon 3 of 3	ENSP00000350425.3	P06727
	ENSG00000285513	ENST00000645414.1		n.169-16T>A		intron	N/A
	ENSG00000305923	ENST00000814126.1		n.135+6664T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152226 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000425 AC: 107 AN: 251476 AF XY: 0.000397

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00189

Gnomad NFE exome AF: 0.000527

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000381 AC: 557 AN: 1461888 Hom.: 0 Cov.: 86 AF XY: 0.000378 AC XY: 275 AN XY: 727244

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00159 AC: 85 AN: 53416

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

European-Non Finnish (NFE) AF: 0.000409 AC: 455 AN: 1112012

Other (OTH) AF: 0.000232 AC: 14 AN: 60396

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152226 Hom.: 0 Cov.: 34 AF XY: 0.000417 AC XY: 31 AN XY: 74368

African (AFR) AF: 0.0000482 AC: 2 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000467 Hom.: 0

Bravo AF: 0.000276

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000321 AC: 39

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.37	N
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.51	T
PhyloP100		-0.047
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.026	D
Vest4		0.14
MVP		0.72
MPC		0.071
ClinPred		0.075	T
GERP RS		3.1
gMVP		0.22
Mutation Taster		=94/6	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: rs147577451; hg19: chr11-116691720;