rs679899

Positions:

• chr2-21028042-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000384.3(APOB):​c.1853C>T​(p.Ala618Val) variant causes a missense change. The variant allele was found at a frequency of 0.47 in 1,608,604 control chromosomes in the GnomAD database, including 187,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.40 (14276 hom., cov: 32)
  • Exomes 𝑓: 0.48 (172976 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 6.75

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0775246E-6).
• BP6: Variant 2-21028042-G-A is Benign according to our data. Variant chr2-21028042-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21028042-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3	c.1853C>T	p.Ala618Val	missense_variant	14/29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.1853C>T	p.Ala618Val	missense_variant	14/29	1	NM_000384.3	ENSP00000233242	P1
APOB	ENST00000399256.4	c.1853C>T	p.Ala618Val	missense_variant	14/17	1		ENSP00000382200
APOB	ENST00000673739.2	c.*1159C>T		3_prime_UTR_variant, NMD_transcript_variant	13/25			ENSP00000501110
APOB	ENST00000673882.2	c.*1159C>T		3_prime_UTR_variant, NMD_transcript_variant	13/23			ENSP00000501253

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60939 AN: 151950 Hom.: 14286 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.853

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.421

GnomAD3 exomes AF: 0.490 AC: 123023 AN: 251266 Hom.: 32976 AF XY: 0.501 AC XY: 67974 AN XY: 135810

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.395

Gnomad ASJ exome AF: 0.380

Gnomad EAS exome AF: 0.852

Gnomad SAS exome AF: 0.614

Gnomad FIN exome AF: 0.568

Gnomad NFE exome AF: 0.469

Gnomad OTH exome AF: 0.469

GnomAD4 exome AF: 0.477 AC: 694384 AN: 1456536 Hom.: 172976 Cov.: 35 AF XY: 0.482 AC XY: 349457 AN XY: 724912

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.390

Gnomad4 ASJ exome AF: 0.370

Gnomad4 EAS exome AF: 0.863

Gnomad4 SAS exome AF: 0.610

Gnomad4 FIN exome AF: 0.558

Gnomad4 NFE exome AF: 0.465

Gnomad4 OTH exome AF: 0.471

GnomAD4 genome AF: 0.401 AC: 60920 AN: 152068 Hom.: 14276 Cov.: 32 AF XY: 0.410 AC XY: 30508 AN XY: 74332

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.377

Gnomad4 ASJ AF: 0.372

Gnomad4 EAS AF: 0.853

Gnomad4 SAS AF: 0.624

Gnomad4 FIN AF: 0.571

Gnomad4 NFE AF: 0.469

Gnomad4 OTH AF: 0.424

Alfa AF: 0.463 Hom.: 41763

Bravo AF: 0.372

TwinsUK AF: 0.460 AC: 1706

ALSPAC AF: 0.475 AC: 1829

ESP6500AA AF: 0.177 AC: 779

ESP6500EA AF: 0.462 AC: 3975

ExAC AF: 0.485 AC: 58942

Asia WGS AF: 0.694 AC: 2411 AN: 3478

EpiCase AF: 0.470

EpiControl AF: 0.469

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 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	-	- -

Hypercholesterolemia, familial, 1 Benign:4

Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hypercholesterolemia, autosomal dominant, type B Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Familial hypobetalipoproteinemia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Familial hypercholesterolemia Benign:2

Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jun 19, 2024	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -

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

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 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

In patients receiving warfarin after mechanical valve replacement, G allele carriers of rs679899 had 6.4 times increased risk of bleeding. likely responsive

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.079	.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.68	.;T
MetaRNN	Benign	0.0000021	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.000014	P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0050	D;T
Sift4G	Pathogenic	0.0	D;D
Vest4		0.55
MPC		0.27
ClinPred		0.016	T
GERP RS		5.7
gMVP		0.68

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

Other links and lift over

dbSNP: rs679899; hg19: chr2-21250914;