rs675

Variant names:

• chr11-116820959-T-A
• rs675
• NM_000482.4:c.1099A>T

Your query was ambiguous. Multiple possible variants found:

• chr11-116820959-T-A
• chr11-116820959-T-C
• chr11-116820959-T-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.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. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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:3
• Conservation: PhyloP100: -0.211
• Publications: 69 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: Benign. The variant received -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 VariationId 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.

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.1099A>T	p.Thr367Ser	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.1099A>T	p.Thr367Ser	missense	Exon 3 of 3	ENSP00000350425.3	P06727
	ENSG00000285513	ENST00000645414.1		n.169-61T>A		intron	N/A
	ENSG00000305923	ENST00000814126.1		n.135+6619T>A		intron	N/A

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

GnomAD2 exomes AF: 0.150 AC: 37745 AN: 251308 AF XY: 0.155

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 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

African (AFR) AF: 0.113 AC: 3782 AN: 33480

American (AMR) AF: 0.100 AC: 4470 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 5569 AN: 26136

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39698

South Asian (SAS) AF: 0.134 AC: 11526 AN: 86254

European-Finnish (FIN) AF: 0.142 AC: 7580 AN: 53408

Middle Eastern (MID) AF: 0.243 AC: 1400 AN: 5768

European-Non Finnish (NFE) AF: 0.196 AC: 217970 AN: 1111984

Other (OTH) AF: 0.175 AC: 10562 AN: 60394

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

African (AFR) AF: 0.116 AC: 4812 AN: 41386

American (AMR) AF: 0.132 AC: 2019 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 765 AN: 3466

East Asian (EAS) AF: 0.00213 AC: 11 AN: 5160

South Asian (SAS) AF: 0.120 AC: 575 AN: 4810

European-Finnish (FIN) AF: 0.136 AC: 1437 AN: 10530

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13636 AN: 67910

Other (OTH) AF: 0.165 AC: 348 AN: 2112

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

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	0.081
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
PhyloP100		-0.21
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
Mutation Taster		=100/0	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: rs675; hg19: chr11-116691675; COSMIC: COSV63360269;