rs147284131
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_020919.4(ALS2):āc.1578A>Gā(p.Thr526=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,614,170 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00017 ( 0 hom., cov: 32)
Exomes š: 0.00029 ( 3 hom. )
Consequence
ALS2
NM_020919.4 synonymous
NM_020919.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0400
Genes affected
ALS2 (HGNC:443): (alsin Rho guanine nucleotide exchange factor ALS2) The protein encoded by this gene contains an ATS1/RCC1-like domain, a RhoGEF domain, and a vacuolar protein sorting 9 (VPS9) domain, all of which are guanine-nucleotide exchange factors that activate members of the Ras superfamily of GTPases. The protein functions as a guanine nucleotide exchange factor for the small GTPase RAB5. The protein localizes with RAB5 on early endosomal compartments, and functions as a modulator for endosomal dynamics. Mutations in this gene result in several forms of juvenile lateral sclerosis and infantile-onset ascending spastic paralysis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BP6
?
Variant 2-201754565-T-C is Benign according to our data. Variant chr2-201754565-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 417160.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}. Variant chr2-201754565-T-C is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-0.04 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000286 (418/1461864) while in subpopulation MID AF= 0.00867 (50/5768). AF 95% confidence interval is 0.00675. There are 3 homozygotes in gnomad4_exome. There are 226 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALS2 | NM_020919.4 | c.1578A>G | p.Thr526= | synonymous_variant | 6/34 | ENST00000264276.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALS2 | ENST00000264276.11 | c.1578A>G | p.Thr526= | synonymous_variant | 6/34 | 1 | NM_020919.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 152188Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000273 AC: 68AN: 249500Hom.: 0 AF XY: 0.000310 AC XY: 42AN XY: 135362
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GnomAD4 exome AF: 0.000286 AC: 418AN: 1461864Hom.: 3 Cov.: 32 AF XY: 0.000311 AC XY: 226AN XY: 727240
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GnomAD4 genome ? AF: 0.000171 AC: 26AN: 152306Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74468
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | ALS2: BP4, BP7 - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 05, 2019 | - - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Feb 18, 2021 | - - |
Infantile-onset ascending hereditary spastic paralysis Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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