rs1553384177

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The ENST00000233242.5(APOB):​c.4089C>G​(p.Tyr1363Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

APOB
ENST00000233242.5 stop_gained

Scores

3
3
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.29
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-21013287-G-C is Pathogenic according to our data. Variant chr2-21013287-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 440525.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
APOBNM_000384.3 linkuse as main transcriptc.4089C>G p.Tyr1363Ter stop_gained 25/29 ENST00000233242.5 NP_000375.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
APOBENST00000233242.5 linkuse as main transcriptc.4089C>G p.Tyr1363Ter stop_gained 25/291 NM_000384.3 ENSP00000233242 P1
APOBENST00000673739.2 linkuse as main transcriptc.*3395C>G 3_prime_UTR_variant, NMD_transcript_variant 24/25 ENSP00000501110
APOBENST00000673882.2 linkuse as main transcript downstream_gene_variant ENSP00000501253

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Familial hypobetalipoproteinemia Pathogenic:1
Pathogenic, no assertion criteria providedresearchLaboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Pathogenic
0.76
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.93
D
MutationTaster
Benign
1.0
A
Vest4
0.96
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553384177; hg19: chr2-21236159; API