2-21006088-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000384.3(APOB):c.10780T>C(p.Trp3594Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000473 in 1,614,056 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (2 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:5
• Conservation: PhyloP100: 2.32

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057753623).
• BP6: Variant 2-21006088-A-G is Benign according to our data. Variant chr2-21006088-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 369881.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=2, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3	c.10780T>C	p.Trp3594Arg	missense_variant	26/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5	c.10780T>C	p.Trp3594Arg	missense_variant	26/29	1	NM_000384.3	P1

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 388 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00890

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000637 AC: 160 AN: 251080 Hom.: 1 AF XY: 0.000442 AC XY: 60 AN XY: 135678

Gnomad AFR exome AF: 0.00868

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000258 AC: 377 AN: 1461742 Hom.: 2 Cov.: 36 AF XY: 0.000223 AC XY: 162 AN XY: 727176

Gnomad4 AFR exome AF: 0.00950

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.00254 AC: 387 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.00254 AC XY: 189 AN XY: 74478

Gnomad4 AFR AF: 0.00887

Gnomad4 AMR AF: 0.000785

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: 0.00236

Alfa AF: 0.000478 Hom.: 1

Bravo AF: 0.00281

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000807 AC: 98

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2020	Variant summary: APOB c.10780T>C (p.Trp3594Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00064 in 251080 control chromosomes, predominantly at a frequency of 0.0087 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 139 fold of the estimated maximal expected allele frequency for a pathogenic variant in APOB causing Familial Hypercholesterolemia phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.10780T>C has been reported in the literature in individuals affected with Hypercholesterolemia (example: Ahmad_2012, Kusters_2013). These reports however, do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign or uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jan 13, 2022

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	0.15
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	0.97	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0040	D
Vest4		0.32
MutPred		0.74		Gain of disorder (P = 0.0028);
MVP		0.85
MPC		0.055
ClinPred		0.096	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs61744288; hg19: chr2-21228960;