rs1553384216

chr2-21013460-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000384.3(APOB):c.3916T>A(p.Ser1306Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52

Genes affected

APOB (HGNC:603): (apolipoprotein B) This gene product is the main apolipoprotein of chylomicrons and low density lipoproteins (LDL), and is the ligand for the LDL receptor. It occurs in plasma as two main isoforms, apoB-48 and apoB-100: the former is synthesized exclusively in the gut and the latter in the liver. The intestinal and the hepatic forms of apoB are encoded by a single gene from a single, very long mRNA. The two isoforms share a common N-terminal sequence. The shorter apoB-48 protein is produced after RNA editing of the apoB-100 transcript at residue 2180 (CAA->UAA), resulting in the creation of a stop codon, and early translation termination. Mutations in this gene or its regulatory region cause hypobetalipoproteinemia, normotriglyceridemic hypobetalipoproteinemia, and hypercholesterolemia due to ligand-defective apoB, diseases affecting plasma cholesterol and apoB levels. [provided by RefSeq, Dec 2019]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37325096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3	c.3916T>A	p.Ser1306Thr	missense_variant	25/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5	c.3916T>A	p.Ser1306Thr	missense_variant	25/29	1	NM_000384.3	P1
APOB	ENST00000673739.2	c.*3222T>A		3_prime_UTR_variant, NMD_transcript_variant	24/25
APOB	ENST00000673882.2	c.*3011T>A		3_prime_UTR_variant, NMD_transcript_variant	23/23

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 27, 2019

Variant of Uncertain Significance due to insufficient evidence: This missense variant (also known as p.Ser1279Thr in the mature protein) is located in the beta 1 domain of the APOB protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	22
Dann	Benign	0.97
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	0.85	D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.16
Sift	Benign	0.20	T
Sift4G	Pathogenic	0.0	D
Vest4		0.51
MutPred		0.29		Gain of relative solvent accessibility (P = 0.0507);
MVP		0.63
MPC		0.26
ClinPred		0.94	D
GERP RS		5.4
gMVP		0.66

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: rs1553384216; hg19: chr2-21236332;