11-116820959-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000482.4(APOA4):c.1099A>G(p.Thr367Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,613,728 control chromosomes in the GnomAD database, including 7 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T367S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (7 hom.)
• Consequence: APOA4 NM_000482.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.211

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00393337).
• BP6: Variant 11-116820959-T-C is Benign according to our data. Variant chr11-116820959-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1669462.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00128 (1864/1461854) while in subpopulation MID AF= 0.0232 (134/5768). AF 95% confidence interval is 0.02. There are 7 homozygotes in gnomad4_exome. There are 993 alleles in male gnomad4_exome subpopulation. Median coverage is 78. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOA4	NM_000482.4	c.1099A>G	p.Thr367Ala	missense_variant	3/3	ENST00000357780.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOA4	ENST00000357780.5	c.1099A>G	p.Thr367Ala	missense_variant	3/3	1	NM_000482.4	P1
	ENST00000645414.1	n.169-61T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000962 AC: 146 AN: 151754 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00125 AC: 313 AN: 251308 Hom.: 2 AF XY: 0.00142 AC XY: 193 AN XY: 135836

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00212

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00128 AC: 1864 AN: 1461854 Hom.: 7 Cov.: 78 AF XY: 0.00137 AC XY: 993 AN XY: 727224

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00235

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00116

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.000942 AC: 143 AN: 151874 Hom.: 0 Cov.: 33 AF XY: 0.000889 AC XY: 66 AN XY: 74210

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000201 Hom.: 1478

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.00135 AC: 164

EpiCase AF: 0.00169

EpiControl AF: 0.00237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	6.1
Dann	Benign	0.56
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.019	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.053
Sift	Benign	0.41	T
Sift4G	Benign	0.34	T
Vest4		0.037
MVP		0.20
MPC		0.051
ClinPred		0.0029	T
GERP RS		0.012
gMVP		0.070

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

LitVar

Other links and lift over

dbSNP: rs675; hg19: chr11-116691675;