rs1800478

Positions:

• chr2-21037264-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.538-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,609,268 control chromosomes in the GnomAD database, including 377 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (189 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (188 hom.)
• Consequence: APOB NM_000384.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001297
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.01

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 (BayesDel_noAF=-0.79).
• BP6: Variant 2-21037264-G-A is Benign according to our data. Variant chr2-21037264-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 334182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21037264-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0892 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3	c.538-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5	c.538-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000384.3	P1
APOB	ENST00000399256.4	c.538-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1
APOB	ENST00000673739.2	c.384-9C>T		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant
APOB	ENST00000673882.2	c.384-9C>T		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0314 AC: 4769 AN: 152108 Hom.: 182 Cov.: 32

Gnomad AFR AF: 0.0911

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0161

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0123

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00834

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0124 AC: 3109 AN: 251038 Hom.: 74 AF XY: 0.0108 AC XY: 1466 AN XY: 135668

Gnomad AFR exome AF: 0.0942

Gnomad AMR exome AF: 0.00820

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0104

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00633

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00939 AC: 13680 AN: 1457042 Hom.: 188 Cov.: 32 AF XY: 0.00904 AC XY: 6548 AN XY: 724694

Gnomad4 AFR exome AF: 0.0933

Gnomad4 AMR exome AF: 0.00942

Gnomad4 ASJ exome AF: 0.0131

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00905

Gnomad4 FIN exome AF: 0.00322

Gnomad4 NFE exome AF: 0.00717

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0316 AC: 4804 AN: 152226 Hom.: 189 Cov.: 32 AF XY: 0.0296 AC XY: 2202 AN XY: 74422

Gnomad4 AFR AF: 0.0917

Gnomad4 AMR AF: 0.0161

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0123

Gnomad4 FIN AF: 0.00255

Gnomad4 NFE AF: 0.00834

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0147 Hom.: 82

Bravo AF: 0.0356

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 21, 2023	- -

Familial hypercholesterolemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jun 23, 2022	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 25, 2018

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. -

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, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.9
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.018
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: rs1800478; hg19: chr2-21260136;