rs565098671
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The ENST00000613296.6(ALMS1):c.11329G>A(p.Glu3777Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,612,418 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 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
ALMS1
ENST00000613296.6 missense
ENST00000613296.6 missense
Scores
7
8
Clinical Significance
Conservation
PhyloP100: 4.05
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=0.21337435).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALMS1 | NM_001378454.1 | c.11329G>A | p.Glu3777Lys | missense_variant | 16/23 | ENST00000613296.6 | NP_001365383.1 | |
ALMS1 | NM_015120.4 | c.11332G>A | p.Glu3778Lys | missense_variant | 16/23 | NP_055935.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.11329G>A | p.Glu3777Lys | missense_variant | 16/23 | 1 | NM_001378454.1 | ENSP00000482968 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152096Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000202 AC: 5AN: 247964Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134478
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1460204Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 726178
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74426
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Alstrom syndrome Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 30, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 03, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3778 of the ALMS1 protein (p.Glu3778Lys). This variant is present in population databases (rs565098671, gnomAD 0.007%). 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: 459848). 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, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 20, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Alstrom syndrome (MIM#203800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes), but has been misannotated as p.(Glu3776Lys). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been previously reported as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;D
Vest4
MVP
ClinPred
D
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