chr2-21012043-A-G

Position:

chr2-21012043-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_000384.3(APOB):c.4825T>C(p.Leu1609Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,614,220 control chromosomes in the GnomAD database, including 11 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 0.0024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0032 ( 11 hom. )

Consequence

APOB
NM_000384.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: -0.277

Variant links:

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]

APOB links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 2-21012043-A-G is Benign according to our data. Variant chr2-21012043-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 477809.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2, Benign=3}. Variant chr2-21012043-A-G is described in Lovd as [Benign]. Variant chr2-21012043-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.277 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 11 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.4825T>C	p.Leu1609Leu	synonymous_variant	26/29	ENST00000233242.5	NP_000375.3	P04114Q7Z7Q0Q59HB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
APOB	ENST00000233242.5 linkuse as main transcript	c.4825T>C	p.Leu1609Leu	synonymous_variant	26/29	1	NM_000384.3	ENSP00000233242.1	P04114
APOB	ENST00000673739.2 linkuse as main transcript	n.*4131T>C		non_coding_transcript_exon_variant	25/25			ENSP00000501110.2	A0A669KB70
APOB	ENST00000673739.2 linkuse as main transcript	n.*4131T>C		3_prime_UTR_variant	25/25			ENSP00000501110.2	A0A669KB70

Frequencies

GnomAD3 genomes

AF:

0.00244

AC:

372

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00389

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00195

AC:

488

AN:

249968

Hom.:

AF XY:

0.00193

AC XY:

261

AN XY:

135036

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00309

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00322

AC:

4713

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

2245

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.00315

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.000412

Gnomad4 NFE exome

AF:

0.00388

Gnomad4 OTH exome

AF:

0.00351

GnomAD4 genome

AF:

0.00244

AC:

372

AN:

152330

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

157

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000649

Gnomad4 AMR

AF:

0.00425

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00390

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00278

Hom.:

Bravo

AF:

0.00291

EpiCase

AF:

0.00409

EpiControl

AF:

0.00356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 14, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	APOB: BP4, BP7 -

Familial hypercholesterolemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 28, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Oct 02, 2023	This is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved and has a PopMax FAF which is greater than expected for this disorder. Therefore this variant has been classified as Likely Benign (BS1, BP4, BP7). -

Hypercholesterolemia, autosomal dominant, type B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Familial hypobetalipoproteinemia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Robarts Research Institute, Western University

Jan 02, 2018

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 23, 2017

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

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.069

DANN

Benign

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over