NM_020919.4:c.4721delT
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_020919.4(ALS2):c.4721delT(p.Val1574AlafsTer44) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
ALS2
NM_020919.4 frameshift
NM_020919.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.25
Publications
3 publications found
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]
ALS2 Gene-Disease associations (from GenCC):
- ALS2-related motor neuron diseaseInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- amyotrophic lateral sclerosis type 2, juvenileInheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
- infantile-onset ascending hereditary spastic paralysisInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
- juvenile primary lateral sclerosisInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
- juvenile amyotrophic lateral sclerosisInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 11 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-201704570-GA-G is Pathogenic according to our data. Variant chr2-201704570-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 4412.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461824Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727210 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461824
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
727210
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33478
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39686
South Asian (SAS)
AF:
AC:
1
AN:
86252
European-Finnish (FIN)
AF:
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111972
Other (OTH)
AF:
AC:
0
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.675
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
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8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
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>80
Age
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Infantile-onset ascending hereditary spastic paralysis Pathogenic:2
Feb 10, 2011
GeneReviews
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:curation
- -
Jan 01, 2003
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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