NM_005502.4:c.4037G>A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_005502.4(ABCA1):c.4037G>A(p.Gly1346Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005502.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCA1 | ENST00000374736.8 | c.4037G>A | p.Gly1346Glu | missense_variant | Exon 28 of 50 | 1 | NM_005502.4 | ENSP00000363868.3 | ||
ABCA1 | ENST00000678995.1 | c.4043G>A | p.Gly1348Glu | missense_variant | Exon 28 of 50 | ENSP00000504612.1 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000115 AC: 29AN: 251466Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135906
GnomAD4 exome AF: 0.0000581 AC: 85AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.0000564 AC XY: 41AN XY: 727240
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74344
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
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Reported as likely pathogenic by another clinical laboratory in ClinVar but additional evidence is not available (ClinVar Variant ID#521460; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30333156, 32041611, 31589614) -
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Cardiovascular phenotype Pathogenic:1
The p.G1346E variant (also known as c.4037G>A), located in coding exon 27 of the ABCA1 gene, results from a G to A substitution at nucleotide position 4037. The glycine at codon 1346 is replaced by glutamic acid, an amino acid with similar properties. This variant has been reported in a subject with Tangier disease who was also noted to be compound heterozygous with the c.4175+1G>T alteration and has been reported in a cohort of subjects with features of Tangier disease (Peloso GM et al. Eur J Hum Genet, 2016 Jun;24:924-30; Geller AS et al. J Lipid Res, 2018 Dec;59:2421-2435). This variant has been identified in the homozygous state, but clinical details were limited (Ambry internal data). This variant does not appear to be associated with disease in a heterozygous state. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Tangier disease;C5231558:Hypoalphalipoproteinemia, primary, 1 Uncertain:1
The c.4037G>A variant has previously been reported as a variant of uncertain significance in a study performed on a cohort of dyslipidemia patients [PMID:32041611]. However, the disease phenotype and the number of affected individuals with this variant have not been specified in the study [PMID:32041611]. This variant has also been reported as a compound heterozygous or heterozygous state in individuals with HDL deficiency [PMID: 30333156, 35460704]. This variant has been deposited in ClinVar [ClinVar ID: 521460] as Likely Pathogenic, Variant of Uncertain Significance, and Likely Benign. The c.4037G>A variant is observed in 58 alleles (0.0098%minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8) suggesting it is not a common benign variant in the populations represented in those databases. The c.4037G>A variant is located in exon 28 of this 50-exon gene and is predicted to replace an evolutionarily conserved glycine amino acid with glutamic acid at position 1346 in the intracellular helices 3 of the encoded protein [PMID: 35460704]. In silico predictions are in favor of damaging effect for p.(Gly1346Glu) the variant [(CADD v1.6 = 27.9, REVEL = 0.833)]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.4037G>A p.(Gly1346Glu) variant identified in ABCA1 is classified as a Variant of UncertainSignificance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at