rs1555511978
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_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 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product 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;
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GAN | NM_022041.4 | c.1502+1G>T | splice_donor_variant | ENST00000648994.2 | NP_071324.1 | |||
GAN | NM_001377486.1 | c.863+1G>T | splice_donor_variant | NP_001364415.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GAN | ENST00000648994.2 | c.1502+1G>T | splice_donor_variant | NM_022041.4 | ENSP00000497351 | P1 | ||||
GAN | ENST00000648349.2 | c.*1210+1G>T | splice_donor_variant, NMD_transcript_variant | ENSP00000498114 | ||||||
GAN | ENST00000650388.1 | c.*859+1G>T | splice_donor_variant, NMD_transcript_variant | ENSP00000498081 | ||||||
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
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | May 22, 2019 | - - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, Cologne University | Apr 25, 2018 | - - |
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