2-21038062-G-C

Variant names:

• chr2-21038062-G-C
• rs6752026
• NM_000384.3:c.433C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000384.3(APOB):​c.433C>G​(p.Pro145Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P145S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.433C>G	p.Pro145Ala	missense_variant	Exon 5 of 29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.433C>G	p.Pro145Ala	missense_variant	Exon 5 of 29	1	NM_000384.3	ENSP00000233242.1
APOB	ENST00000399256.4	c.433C>G	p.Pro145Ala	missense_variant	Exon 5 of 17	1		ENSP00000382200.4
APOB	ENST00000673739.2	n.384-807C>G		intron_variant	Intron 4 of 24			ENSP00000501110.2
APOB	ENST00000673882.2	n.384-807C>G		intron_variant	Intron 4 of 22			ENSP00000501253.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251488 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

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

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Uncertain:1

Dec 10, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.433C>G (p.Pro145Ala) variant identified in the APOB gene substitutes a conserved Proline for Alanine at amino acid 145/4564 (exon 5/29). This variant is absent from gnomAD(v3.1.2) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score:0.056) and Benign (REVEL; 0.215) to the function of the canonical transcript. This variant is absent from ClinVar, and to our current knowledge has not been reported in individuals with hypercholesterolemia. Given the lack of compelling evidence for its pathogenicity, the c.433C>G (p.Pro145Ala) variant identified in the APOB gene is reported as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	.;T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-0.76	T
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Benign	0.21
Sift	Benign	0.071	T;T
Sift4G	Benign	0.22	T;D
Vest4		0.50
MutPred		0.56		Loss of glycosylation at P145 (P = 0.0721);Loss of glycosylation at P145 (P = 0.0721);
MVP		0.72
MPC		0.14
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.71

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: rs6752026; hg19: chr2-21260934;