rs72653083

Variant names:

• chr2-21012043-A-G
• rs72653083
• NM_000384.3:c.4825T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000384.3(APOB):​c.4825T>C​(p.Leu1609Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,614,220 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1609L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (11 hom.)
• Consequence: APOB NM_000384.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12
• Conservation: PhyloP100: -0.277
• Publications: 5 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-21012043-A-G is Benign according to our data. Variant chr2-21012043-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 477809.
• BP7: Synonymous conserved (PhyloP=-0.277 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 11 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	NM_000384.3	MANE Select	c.4825T>C	p.Leu1609Leu	synonymous	Exon 26 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.4825T>C	p.Leu1609Leu	synonymous	Exon 26 of 29	ENSP00000233242.1	P04114
	APOB	ENST00000673739.2		n.*4131T>C		non_coding_transcript_exon	Exon 25 of 25	ENSP00000501110.2	A0A669KB70
	APOB	ENST00000673739.2		n.*4131T>C		3_prime_UTR	Exon 25 of 25	ENSP00000501110.2	A0A669KB70

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 372 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00389

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00195 AC: 488 AN: 249968 AF XY: 0.00193

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00309

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00322 AC: 4713 AN: 1461890 Hom.: 11 Cov.: 35 AF XY: 0.00309 AC XY: 2245 AN XY: 727244

African (AFR) AF: 0.000597 AC: 20 AN: 33478

American (AMR) AF: 0.00315 AC: 141 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00388 AC: 4312 AN: 1112012

Other (OTH) AF: 0.00351 AC: 212 AN: 60396

GnomAD4 genome AF: 0.00244 AC: 372 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.00211 AC XY: 157 AN XY: 74474

African (AFR) AF: 0.000649 AC: 27 AN: 41584

American (AMR) AF: 0.00425 AC: 65 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00390 AC: 265 AN: 68034

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00282 Hom.: 1

Bravo AF: 0.00291

EpiCase AF: 0.00409

EpiControl AF: 0.00356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Familial hypercholesterolemia (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Familial hypobetalipoproteinemia 1 (1)
-	1	-	Hypercholesterolemia, autosomal dominant, type B (1)
-	-	1	Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 (1)
-	-	1	Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.069
DANN	Benign	0.47
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs72653083; hg19: chr2-21234915;