rs1193057149

Variant names:

• chr2-21003344-G-A
• rs1193057149
• NM_000384.3:c.12088-10C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000384.3(APOB):​c.12088-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: APOB NM_000384.3 intron
• Scores: Splicing: ADA: 0.00002305
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.233
• Publications: 0 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, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial hypobetalipoproteinemia 1

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-21003344-G-A is Benign according to our data. Variant chr2-21003344-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 477796.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	NM_000384.3	MANE Select	c.12088-10C>T		intron	N/A	NP_000375.3	P04114

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.12088-10C>T		intron	N/A	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes AF: 0.0000748 AC: 11 AN: 147070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000759

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000300

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000598 AC: 136 AN: 227454 AF XY: 0.000548

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.000649

Gnomad EAS exome AF: 0.000242

Gnomad FIN exome AF: 0.000106

Gnomad NFE exome AF: 0.000841

Gnomad OTH exome AF: 0.000747

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000260 AC: 372 AN: 1432208 Hom.: 0 Cov.: 34 AF XY: 0.000240 AC XY: 171 AN XY: 712664

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

African (AFR) AF: 0.00251 AC: 80 AN: 31830

American (AMR) AF: 0.00125 AC: 50 AN: 39940

Ashkenazi Jewish (ASJ) AF: 0.000592 AC: 15 AN: 25342

East Asian (EAS) AF: 0.0000761 AC: 3 AN: 39400

South Asian (SAS) AF: 0.000294 AC: 24 AN: 81508

European-Finnish (FIN) AF: 0.000101 AC: 5 AN: 49684

Middle Eastern (MID) AF: 0.000714 AC: 4 AN: 5602

European-Non Finnish (NFE) AF: 0.000152 AC: 167 AN: 1099834

Other (OTH) AF: 0.000406 AC: 24 AN: 59068

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000748 AC: 11 AN: 147070 Hom.: 0 Cov.: 32 AF XY: 0.0000840 AC XY: 6 AN XY: 71392

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

African (AFR) AF: 0.0000500 AC: 2 AN: 39962

American (AMR) AF: 0.00 AC: 0 AN: 14834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

East Asian (EAS) AF: 0.00 AC: 0 AN: 5038

South Asian (SAS) AF: 0.00 AC: 0 AN: 4652

European-Finnish (FIN) AF: 0.000759 AC: 7 AN: 9228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000300 AC: 2 AN: 66690

Other (OTH) AF: 0.00 AC: 0 AN: 2036

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000000226485), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00439 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.0
DANN	Benign	0.20
PhyloP100		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.058
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1193057149;

hg19: chr2-21226216;