2-21009583-A-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_000384.3(APOB):c.7285T>A(p.Ser2429Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000724 in 1,613,954 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000598 AC: 91AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000690 AC: 173AN: 250820Hom.: 0 AF XY: 0.000738 AC XY: 100AN XY: 135544
GnomAD4 exome AF: 0.000737 AC: 1077AN: 1461642Hom.: 1 Cov.: 60 AF XY: 0.000758 AC XY: 551AN XY: 727132
GnomAD4 genome AF: 0.000597 AC: 91AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35AN XY: 74484
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:3
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Identified in at least one individual with hypertriglyceridemia and possible FH in published literature (Johansen et al., 2010; Radovica-Spalvine et al., 2015); Identified in two unrelated families with FH, who also harbored other FH-related variants that were suspected to cause disease (Rabacchi et al., 2016; Alnouri et al., 20018); In one family, three individuals who were heterozygous for the S2429T variant in the APOB gene in addition to at least one pathogenic variant in the LDLR gene had lower LDL-C levels than family members who did not harbor the S2429T variant, leading the authors to hypothesize that the S2429T variant may have an LDL-lowering effect (Rabacchi et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID#218448; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 33069457, 20657596, 26415676, 27578127, 27153395, 30270081) -
APOB: BP4 -
not specified Uncertain:2Benign:1
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Few reports, no segs, ExAC: 0.1% (92/66598) European chromosomes -
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Hypercholesterolemia, autosomal dominant, type B Uncertain:2
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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Hypercholesterolemia, familial, 1 Uncertain:2
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Hypercholesterolemia Uncertain:1
Found in patient having exome sequencing for an unrelated indication. No known history hypercholesterolemia. -
Familial hypobetalipoproteinemia 1 Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Familial hypercholesterolemia Benign:1
Likely Benign based on current evidence: This missense variant (also known as p.Ser2402Thr in the mature protein) is located in the alpha 2 domain of the APOB protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in a Latvian individual with suspected hypercholesterolemia (PMID: 26415676). In an Italian family with hypercholesterolemia caused by biallelic LDLR mutations, this variant was suggested to have LDL-C lowering effect (PMID: 27578127). This variant has been identified in 136/126166 non-Finnish European chromosomes (0.11%) and 39/10136 Ashkenazi Jewish chromosomes (0.38%) in the general population by the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for the disorder based on prevalence, penetrance, and genetic heterogeneity. Based on available evidence, this variant is classified as Likely Benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at