rs376602710

chr2-21029968-G-Achr2-21029968-G-C

Variant summary

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

The NM_000384.3(APOB):c.1400C>T(p.Ala467Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. A467G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.44

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=0.41006535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3	c.1400C>T	p.Ala467Val	missense_variant	11/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5	c.1400C>T	p.Ala467Val	missense_variant	11/29	1	NM_000384.3	P1
APOB	ENST00000399256.4	c.1400C>T	p.Ala467Val	missense_variant	11/17	1
APOB	ENST00000673739.2	c.*706C>T		3_prime_UTR_variant, NMD_transcript_variant	10/25
APOB	ENST00000673882.2	c.*706C>T		3_prime_UTR_variant, NMD_transcript_variant	10/23

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461694 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 467 of the APOB protein (p.Ala467Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APOB protein function. ClinVar contains an entry for this variant (Variation ID: 946294). This variant has not been reported in the literature in individuals affected with APOB-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Uncertain	0.0010	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.23
MutPred		0.51		Gain of catalytic residue at A467 (P = 0.007);Gain of catalytic residue at A467 (P = 0.007);
MVP		0.79
MPC		0.11
ClinPred		0.94	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.22

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: rs376602710; hg19: chr2-21252840;