rs45630562
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001378454.1(ALMS1):c.11660T>C(p.Ile3887Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000035 ( 0 hom. )
Consequence
ALMS1
NM_001378454.1 missense
NM_001378454.1 missense
Scores
2
1
12
Clinical Significance
Conservation
PhyloP100: 2.97
Genes affected
ALMS1 (HGNC:428): (ALMS1 centrosome and basal body associated protein) This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.15219903).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALMS1 | NM_001378454.1 | c.11660T>C | p.Ile3887Thr | missense_variant | 17/23 | ENST00000613296.6 | |
ALMS1 | NM_015120.4 | c.11663T>C | p.Ile3888Thr | missense_variant | 17/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.11660T>C | p.Ile3887Thr | missense_variant | 17/23 | 1 | NM_001378454.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 248850Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 135000
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GnomAD4 exome AF: 0.0000349 AC: 51AN: 1461234Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 726940
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Alstrom syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This sequence change replaces isoleucine with threonine at codon 3888 of the ALMS1 protein (p.Ile3888Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs45630562, gnomAD 0.004%). This missense change has been observed in individuals with Alstrom syndrome (PMID: 17594715). ClinVar contains an entry for this variant (Variation ID: 506260). 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 18, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 16, 2021 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 17, 2018 | The p.Ile3888Thr variant in ALMS1 has been reported in 3 individuals with Alstro m syndrome, two of whom carried a pathogenic variant on the other allele. Howeve r, the third individual carried a truncating variant on the same copy (in cis) a s the p.Ile3888Thr variant, and had another pathogenic variant on the other copy of the gene (Marshall 2007). This variant has also been identified in 5/111172 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; dbSNP rs45630562); though this frequency is not high enough t o rule out a pathogenic role. Furthermore, isoleucine (Ile) at position 3888 is not conserved in mammals or evolutionarily distant species and 1 mammal (Gibbon) carries a threonine (Thr) at this position, raising the possibility that this c hange may be tolerated. Additional computational prediction tools support that t he variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ile3888Thr variant is uncertain. ACMG/AMP criteria applied: PM3_Strong, PM2, PP1, BP2, BP4. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 28, 2023 | Variant summary: ALMS1 c.11657T>C (p.Ile3886Thr), also known as c.11663T>C (p.Ile3888Thr), results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 248850 control chromosomes (gnomAD). c.11657T>C has been reported in the literature in individuals affected with Alstrom Syndrome (e.g. Marshall_2007, Pereiro_2011, Ozanturk_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: all five classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 10, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25296579, 25846608, 17594715) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 14, 2023 | The p.I3888T variant (also known as c.11663T>C), located in coding exon 17 of the ALMS1 gene, results from a T to C substitution at nucleotide position 11663. The isoleucine at codon 3888 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in subjects with features of Alstrom syndrome (Marshall JD et al. Hum Mutat, 2007 Nov;28:1114-23; Pereiro I et al. Eur J Hum Genet, 2011 Apr;19:485-8). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N
PrimateAI
Benign
T
Sift4G
Benign
T;T
Vest4
MVP
ClinPred
T
GERP RS
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