rs55814314
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_005502.4(ABCA1):c.3204C>T(p.Arg1068=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000828 in 1,614,204 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00045 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00087 ( 13 hom. )
Consequence
ABCA1
NM_005502.4 synonymous
NM_005502.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.25
Genes affected
ABCA1 (HGNC:29): (ATP binding cassette subfamily A member 1) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. With cholesterol as its substrate, this protein functions as a cholesteral efflux pump in the cellular lipid removal pathway. Mutations in both alleles of this gene cause Tangier disease and familial high-density lipoprotein (HDL) deficiency. [provided by RefSeq, Sep 2019]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.39).
BP6
?
Variant 9-104819623-G-A is Benign according to our data. Variant chr9-104819623-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 364420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104819623-G-A is described in Lovd as [Benign]. Variant chr9-104819623-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=1.25 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000453 (69/152310) while in subpopulation SAS AF= 0.00497 (24/4830). AF 95% confidence interval is 0.00343. There are 1 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 13 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA1 | NM_005502.4 | c.3204C>T | p.Arg1068= | synonymous_variant | 22/50 | ENST00000374736.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA1 | ENST00000374736.8 | c.3204C>T | p.Arg1068= | synonymous_variant | 22/50 | 1 | NM_005502.4 | P1 | |
ABCA1 | ENST00000678995.1 | c.3204C>T | p.Arg1068= | synonymous_variant | 22/50 |
Frequencies
GnomAD3 genomes ? AF: 0.000447 AC: 68AN: 152192Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00132 AC: 333AN: 251478Hom.: 6 AF XY: 0.00170 AC XY: 231AN XY: 135916
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GnomAD4 exome AF: 0.000867 AC: 1268AN: 1461894Hom.: 13 Cov.: 33 AF XY: 0.00110 AC XY: 797AN XY: 727248
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GnomAD4 genome ? AF: 0.000453 AC: 69AN: 152310Hom.: 1 Cov.: 32 AF XY: 0.000550 AC XY: 41AN XY: 74490
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 22, 2021 | This variant is associated with the following publications: (PMID: 22923420, 15935359) - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 20, 2017 | Variant summary: The ABCA1 c.3204C>T (p.Arg1068Arg) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 183/127812 control chromosomes (3 homozygotes) at a frequency of 0.0014318, which is approximately 115 times the estimated maximal expected allele frequency of a pathogenic ABCA1 variant (0.0000125), suggesting this variant is likely a benign polymorphism. This variant has not, to our knowledge, been reported in any affected individuals via publications. In addition, one clinical diagnostic laboratory classified this variant as likely benign. Taken together, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2020 | This alteration is classified as 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. - |
Hypoalphalipoproteinemia, primary, 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Tangier disease Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at