rs754264874
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5
The NM_000384.3(APOB):c.10519C>T(p.Arg3507Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3507P) has been classified as Likely benign.
Frequency
Consequence
NM_000384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APOB | NM_000384.3 | c.10519C>T | p.Arg3507Trp | missense_variant | 26/29 | ENST00000233242.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APOB | ENST00000233242.5 | c.10519C>T | p.Arg3507Trp | missense_variant | 26/29 | 1 | NM_000384.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152132Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250624Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135442
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461710Hom.: 0 Cov.: 36 AF XY: 0.00000688 AC XY: 5AN XY: 727158
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152132Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, type B Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Sep 26, 2019 | The c.10519C>T (p.Arg3507Trp) variant in the APOB gene has been reported in an individual with mild to moderate hypercholesterolemia (PMID: 11115503) and in Dutch patients with FH (PMID: 16250003). Also known as p.Arg3480Trp, functional studies showed that this variant reduced the binding of LDL to the LDL receptor (PMID: 11115503). This variant is observed at a frequency of 6/282024 in the gnomAD population database. A different missense change at the same amino acid, p.Arg3507Pro, has also been reported in individuals with hypercholesterolemia (PMID: 7882518, 16250003). In light of the currently available data this c.10519C>T (p.Arg3507Trp) variant is classified as likely pathogenic. - |
Hypercholesterolemia, familial, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | curation;literature only | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Sep 03, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at