rs119485092
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The NM_022041.4(GAN):c.413G>A(p.Arg138His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_022041.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAN | NM_022041.4 | c.413G>A | p.Arg138His | missense_variant | 3/11 | ENST00000648994.2 | |
GAN | NM_001377486.1 | c.-227G>A | 5_prime_UTR_variant | 2/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAN | ENST00000648994.2 | c.413G>A | p.Arg138His | missense_variant | 3/11 | NM_022041.4 | P1 | ||
GAN | ENST00000674788.1 | n.538G>A | non_coding_transcript_exon_variant | 3/3 | |||||
GAN | ENST00000648349.2 | c.*121G>A | 3_prime_UTR_variant, NMD_transcript_variant | 2/10 | |||||
GAN | ENST00000650388.1 | c.168-2250G>A | intron_variant, NMD_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251490Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135920
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461724Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727170
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Giant axonal neuropathy 1 Pathogenic:2Uncertain:2
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2000 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 18, 2022 | ClinVar contains an entry for this variant (Variation ID: 5035). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GAN function (PMID: 24758703). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with a mild form of giant axonal neuropathy (PMID: 11053687, 11062483). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs119485092, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 138 of the GAN protein (p.Arg138His). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at