rs693

Positions:

• chr2-21009323-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000384.3(APOB):​c.7545C>T​(p.Thr2515=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,613,650 control chromosomes in the GnomAD database, including 181,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12425 hom., cov: 32)
  • Exomes 𝑓: 0.47 (168652 hom.)
• Consequence: APOB NM_000384.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 0.126

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 2-21009323-G-A is Benign according to our data. Variant chr2-21009323-G-A is described in ClinVar as [Benign]. Clinvar id is 128425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21009323-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.126 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3	c.7545C>T	p.Thr2515=	synonymous_variant	26/29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.7545C>T	p.Thr2515=	synonymous_variant	26/29	1	NM_000384.3	ENSP00000233242	P1

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57860 AN: 151844 Hom.: 12425 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.534

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.0547

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.372

GnomAD3 exomes AF: 0.389 AC: 97584 AN: 251146 Hom.: 21368 AF XY: 0.391 AC XY: 53030 AN XY: 135726

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.381

Gnomad ASJ exome AF: 0.346

Gnomad EAS exome AF: 0.0572

Gnomad SAS exome AF: 0.267

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.501

Gnomad OTH exome AF: 0.418

GnomAD4 exome AF: 0.467 AC: 683229 AN: 1461688 Hom.: 168652 Cov.: 66 AF XY: 0.462 AC XY: 335706 AN XY: 727126

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.382

Gnomad4 ASJ exome AF: 0.353

Gnomad4 EAS exome AF: 0.0530

Gnomad4 SAS exome AF: 0.273

Gnomad4 FIN exome AF: 0.411

Gnomad4 NFE exome AF: 0.517

Gnomad4 OTH exome AF: 0.428

GnomAD4 genome AF: 0.381 AC: 57866 AN: 151962 Hom.: 12425 Cov.: 32 AF XY: 0.372 AC XY: 27619 AN XY: 74280

Gnomad4 AFR AF: 0.229

Gnomad4 AMR AF: 0.413

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.0546

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.386

Gnomad4 NFE AF: 0.500

Gnomad4 OTH AF: 0.370

Alfa AF: 0.459 Hom.: 29043

Bravo AF: 0.375

Asia WGS AF: 0.165 AC: 578 AN: 3478

EpiCase AF: 0.486

EpiControl AF: 0.485

ClinVar

Significance: Benign

Submissions summary: Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hypercholesterolemia, autosomal dominant, type B Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial hypobetalipoproteinemia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial hypercholesterolemia Benign:2

Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jun 21, 2022	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hypercholesterolemia, familial, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 27, 2017

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2015

This alteration is classified as 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. -

Warfarin response Other:1

drug response, no assertion criteria provided

research

Pharmacogenomics Lab, Chungbuk National University

Aug 31, 2010

- likely responsive

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.1
DANN	Benign	0.86

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: rs693; hg19: chr2-21232195; COSMIC: COSV51935946;