rs12720851

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000384.3(APOB):c.11904-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00869 in 1,613,920 control chromosomes in the GnomAD database, including 522 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 220 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 302 hom. )

Consequence

APOB
NM_000384.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001423

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.0620

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 2-21004459-G-A is Benign according to our data. Variant chr2-21004459-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21004459-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.11904-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5 linkuse as main transcript	c.11904-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000384.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0338

AC:

5135

AN:

152100

Hom.:

217

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0217

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.00310

Gnomad OTH

AF:

0.0363

GnomAD3 exomes

AF:

0.0115

AC:

2883

AN:

251278

Hom.:

116

AF XY:

0.00942

AC XY:

1279

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.113

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00364

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.00607

AC:

8873

AN:

1461702

Hom.:

302

Cov.:

AF XY:

0.00577

AC XY:

4195

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.117

Gnomad4 AMR exome

AF:

0.0126

Gnomad4 ASJ exome

AF:

0.00953

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00153

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00257

Gnomad4 OTH exome

AF:

0.0133

GnomAD4 genome

AF:

0.0338

AC:

5146

AN:

152218

Hom.:

220

Cov.:

AF XY:

0.0324

AC XY:

2410

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.107

Gnomad4 AMR

AF:

0.0217

Gnomad4 ASJ

AF:

0.0144

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00310

Gnomad4 OTH

AF:

0.0359

Alfa

AF:

0.0124

Hom.:

Bravo

AF:

0.0393

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.00562

EpiControl

AF:

0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Hypercholesterolemia, autosomal dominant, type B

Benign:1

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. -

Hypercholesterolemia, familial, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Robarts Research Institute, Western University

Jan 02, 2018

- -

Familial hypobetalipoproteinemia 1

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Familial hypercholesterolemia

Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Feb 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

Cadd

Benign

2.7

Dann

Benign

0.76

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000014

dbscSNV1_RF

Benign

0.0080

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