rs1555511978
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_022041.4(GAN):c.1502+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 30)
Consequence
GAN
NM_022041.4 splice_donor
NM_022041.4 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.64
Genes affected
GAN (HGNC:4137): (gigaxonin) This gene encodes a member of the cytoskeletal BTB/kelch (Broad-Complex, Tramtrack and Bric a brac) repeat family. The encoded protein plays a role in neurofilament architecture and is involved in mediating the ubiquitination and degradation of some proteins. Defects in this gene are a cause of giant axonal neuropathy (GAN). [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.07134894 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.1, offset of -41, new splice context is: atgGTaact. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 16-81365479-G-T is Pathogenic according to our data. Variant chr16-81365479-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 465389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81365479-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAN | NM_022041.4 | c.1502+1G>T | splice_donor_variant | ENST00000648994.2 | |||
GAN | NM_001377486.1 | c.863+1G>T | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAN | ENST00000648994.2 | c.1502+1G>T | splice_donor_variant | NM_022041.4 | P1 | ||||
GAN | ENST00000648349.2 | c.*1210+1G>T | splice_donor_variant, NMD_transcript_variant | ||||||
GAN | ENST00000650388.1 | c.*859+1G>T | splice_donor_variant, NMD_transcript_variant | ||||||
GAN | ENST00000567335.1 | n.60+1G>T | splice_donor_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 30
GnomAD4 genome
?
Cov.:
30
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Giant axonal neuropathy 1 Pathogenic:2Uncertain:2
Pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, Cologne University | Apr 25, 2018 | - - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 02, 2017 | This sequence change affects a donor splice site in intron 9 of the GAN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in GAN are known to be pathogenic (PMID: 11062483). This variant has been reported in the homozygous state in individuals with giant axonal neuropathy (GAN) (PMID: 15897506). Experimental studies have shown that this sequence change results in abnormal sub-cellular aggregates in cells derived from patients carrying this variant (PMID: 12668605). For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | May 22, 2019 | - - |
See cases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Dec 20, 2021 | ACMG categories: PVS1,PM2 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -42
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at