rs141888564

Variant names:

• chr2-21033498-C-A
• rs141888564
• NM_000384.3:c.925G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-21033498-C-A
• chr2-21033498-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000384.3(APOB):​c.925G>T​(p.Ala309Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A309T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.708
• Publications: 8 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: ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial hypobetalipoproteinemia 1

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24347565).

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.925G>T	p.Ala309Ser	missense	Exon 9 of 29	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.925G>T	p.Ala309Ser	missense	Exon 9 of 29	ENSP00000233242.1	P04114
	APOB	ENST00000399256.4	TSL:1	c.925G>T	p.Ala309Ser	missense	Exon 9 of 17	ENSP00000382200.4	A8MUN2
	APOB	ENST00000673739.2		n.*231G>T		non_coding_transcript_exon	Exon 8 of 25	ENSP00000501110.2	A0A669KB70

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251452 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111966

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.037
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.71
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.15
Sift	Benign	0.37	T
Sift4G	Benign	0.21	T
Vest4		0.12
MutPred		0.53		Gain of phosphorylation at A309 (P = 0.029)
MVP		0.58
MPC		0.18
ClinPred		0.87	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.38
Mutation Taster		=88/12	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: rs141888564; hg19: chr2-21256370;