rs200462734
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001378454.1(ALMS1):c.12044G>A(p.Gly4015Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000384 in 1,614,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4015V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001378454.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALMS1 | NM_001378454.1 | c.12044G>A | p.Gly4015Asp | missense_variant | 19/23 | ENST00000613296.6 | |
ALMS1 | NM_015120.4 | c.12047G>A | p.Gly4016Asp | missense_variant | 19/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.12044G>A | p.Gly4015Asp | missense_variant | 19/23 | 1 | NM_001378454.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000217 AC: 33AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000216 AC: 54AN: 250210Hom.: 0 AF XY: 0.000214 AC XY: 29AN XY: 135634
GnomAD4 exome AF: 0.000402 AC: 587AN: 1461834Hom.: 0 Cov.: 74 AF XY: 0.000402 AC XY: 292AN XY: 727212
GnomAD4 genome ? AF: 0.000217 AC: 33AN: 152334Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15AN XY: 74498
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 14, 2019 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ALMS1 p.Gly4014Asp variant was not identified in the literature but was identified in dbSNP (ID: rs200462734) and ClinVar (uncertain significance by GeneDx and Invitae). The variant was identified in control databases in 60 of 281608 chromosomes at a frequency of 0.0002131 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 50 of 128624 chromosomes (freq: 0.000389), Other in 2 of 7164 chromosomes (freq: 0.000279), African in 2 of 24396 chromosomes (freq: 0.000082), European (Finnish) in 2 of 25106 chromosomes (freq: 0.00008), South Asian in 2 of 30616 chromosomes (freq: 0.000065) and Latino in 2 of 35430 chromosomes (freq: 0.000056), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Gly4014 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Alstrom syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 27, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 4016 of the ALMS1 protein (p.Gly4016Asp). This variant is present in population databases (rs200462734, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 373262). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 23, 2016 | A variant of uncertain significance has been identified in the ALMS1 gene. The G4016D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Nevertheless, the G4016D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 04, 2023 | The p.G4016D variant (also known as c.12047G>A), located in coding exon 19 of the ALMS1 gene, results from a G to A substitution at nucleotide position 12047. The glycine at codon 4016 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at