NM_000384.3:c.12088-13delT

Variant names:

• chr2-21003346-GA-G
• rs751121092
• NM_000384.3:c.12088-13delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000384.3(APOB):​c.12088-13delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,174,020 control chromosomes in the GnomAD database, including 31 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (5 hom., cov: 32)
  • Exomes 𝑓: 0.013 (26 hom.)
• Consequence: APOB NM_000384.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.342
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, autosomal dominant, type B

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• familial hypobetalipoproteinemia 1

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-21003346-GA-G is Benign according to our data. Variant chr2-21003346-GA-G is described in ClinVar as Benign. ClinVar VariationId is 490382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00358 (493/137590) while in subpopulation EAS AF = 0.0426 (205/4808). AF 95% confidence interval is 0.0379. There are 5 homozygotes in GnomAd4. There are 252 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	NM_000384.3	MANE Select	c.12088-13delT		intron	N/A	NP_000375.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.12088-13delT		intron	N/A	ENSP00000233242.1

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 491 AN: 137524 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00232

Gnomad ASJ AF: 0.00646

Gnomad EAS AF: 0.0425

Gnomad SAS AF: 0.00272

Gnomad FIN AF: 0.000509

Gnomad MID AF: 0.0105

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00789

GnomAD2 exomes AF: 0.0184 AC: 2615 AN: 141744 AF XY: 0.0180

Gnomad AFR exome AF: 0.00527

Gnomad AMR exome AF: 0.0145

Gnomad ASJ exome AF: 0.0266

Gnomad EAS exome AF: 0.0830

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.0214

GnomAD4 exome AF: 0.0134 AC: 13904 AN: 1036430 Hom.: 26 Cov.: 29 AF XY: 0.0131 AC XY: 6722 AN XY: 513868

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0128 AC: 293 AN: 22828

American (AMR) AF: 0.0107 AC: 316 AN: 29532

Ashkenazi Jewish (ASJ) AF: 0.0148 AC: 254 AN: 17156

East Asian (EAS) AF: 0.0540 AC: 1491 AN: 27616

South Asian (SAS) AF: 0.0116 AC: 676 AN: 58098

European-Finnish (FIN) AF: 0.0116 AC: 393 AN: 33870

Middle Eastern (MID) AF: 0.0133 AC: 58 AN: 4374

European-Non Finnish (NFE) AF: 0.0122 AC: 9747 AN: 801148

Other (OTH) AF: 0.0162 AC: 676 AN: 41808

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00358 AC: 493 AN: 137590 Hom.: 5 Cov.: 32 AF XY: 0.00379 AC XY: 252 AN XY: 66410

African (AFR) AF: 0.00245 AC: 92 AN: 37500

American (AMR) AF: 0.00231 AC: 32 AN: 13834

Ashkenazi Jewish (ASJ) AF: 0.00646 AC: 21 AN: 3250

East Asian (EAS) AF: 0.0426 AC: 205 AN: 4808

South Asian (SAS) AF: 0.00273 AC: 12 AN: 4390

European-Finnish (FIN) AF: 0.000509 AC: 4 AN: 7852

Middle Eastern (MID) AF: 0.0150 AC: 4 AN: 266

European-Non Finnish (NFE) AF: 0.00172 AC: 108 AN: 62934

Other (OTH) AF: 0.00782 AC: 15 AN: 1918

Alfa AF: 0.0251 Hom.: 0

Bravo AF: 0.00370

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypercholesterolemia, familial, 1 Benign:1

Aug 28, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Sep 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs751121092; hg19: chr2-21226218; COSMIC: COSV51926493; COSMIC: COSV51926493;