rs138880920
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_005502.4(ABCA1):āc.2328G>Cā(p.Lys776Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,613,890 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0020 ( 0 hom., cov: 33)
Exomes š: 0.0028 ( 25 hom. )
Consequence
ABCA1
NM_005502.4 missense
NM_005502.4 missense
Scores
2
11
5
Clinical Significance
Conservation
PhyloP100: 1.18
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 -20 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.036502987).
BP6
?
Variant 9-104826957-C-G is Benign according to our data. Variant chr9-104826957-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 364430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104826957-C-G is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00196 (299/152346) while in subpopulation SAS AF= 0.00932 (45/4830). AF 95% confidence interval is 0.00716. There are 0 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 25 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA1 | NM_005502.4 | c.2328G>C | p.Lys776Asn | missense_variant | 16/50 | ENST00000374736.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA1 | ENST00000374736.8 | c.2328G>C | p.Lys776Asn | missense_variant | 16/50 | 1 | NM_005502.4 | P1 | |
ABCA1 | ENST00000678995.1 | c.2328G>C | p.Lys776Asn | missense_variant | 16/50 | ||||
ABCA1 | ENST00000494467.1 | n.501G>C | non_coding_transcript_exon_variant | 3/4 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00196 AC: 298AN: 152228Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00327 AC: 819AN: 250436Hom.: 7 AF XY: 0.00378 AC XY: 512AN XY: 135412
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GnomAD4 exome AF: 0.00276 AC: 4037AN: 1461544Hom.: 25 Cov.: 32 AF XY: 0.00296 AC XY: 2151AN XY: 727062
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GnomAD4 genome ? AF: 0.00196 AC: 299AN: 152346Hom.: 0 Cov.: 33 AF XY: 0.00204 AC XY: 152AN XY: 74508
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ExAC
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Asia WGS
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | ABCA1: BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 2020 | This variant is associated with the following publications: (PMID: 30333156, 28870971, 26255038, 16226177, 24497850, 21875686) - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 22, 2022 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 10, 2021 | 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. - |
Hypoalphalipoproteinemia, primary, 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 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
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Loss of methylation at K776 (P = 0.0148);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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