rs76202659

chr2-21030027-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000384.3(APOB):c.1353-12C>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 0.00267 in 1,551,580 control chromosomes in the GnomAD database, including 80 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 0.013 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (40 hom.)
• Consequence: APOB NM_000384.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008316
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.0720

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-21030027-G-A is Benign according to our data. Variant chr2-21030027-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265880.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=2, Likely_benign=1}. Variant chr2-21030027-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1997/152312) while in subpopulation AFR AF= 0.0456 (1895/41556). AF 95% confidence interval is 0.0439. There are 40 homozygotes in gnomad4. There are 946 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 40 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3	c.1353-12C>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.1353-12C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000384.3	P1
APOB	ENST00000399256.4	c.1353-12C>T		splice_polypyrimidine_tract_variant, intron_variant		1
APOB	ENST00000673739.2	c.*659-12C>T		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant
APOB	ENST00000673882.2	c.*659-12C>T		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1990 AN: 152194 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0456

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00372 AC: 934 AN: 251290 Hom.: 16 AF XY: 0.00265 AC XY: 360 AN XY: 135806

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00154 AC: 2152 AN: 1399268 Hom.: 40 Cov.: 24 AF XY: 0.00141 AC XY: 984 AN XY: 700330

Gnomad4 AFR exome AF: 0.0496

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.00190

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000435

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000100

Gnomad4 OTH exome AF: 0.00390

GnomAD4 genome AF: 0.0131 AC: 1997 AN: 152312 Hom.: 40 Cov.: 33 AF XY: 0.0127 AC XY: 946 AN XY: 74492

Gnomad4 AFR AF: 0.0456

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00761 Hom.: 3

Bravo AF: 0.0148

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hypercholesterolemia, autosomal dominant, type B Benign:1

Benign, 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 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2019

- -

Familial hypobetalipoproteinemia 1 Benign:1

Likely benign, 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 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	-0.73
Cadd	Benign	11
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000083
dbscSNV1_RF	Benign	0.0
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: rs76202659; hg19: chr2-21252899;