rs1555511093
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_022041.4(GAN):c.374T>C(p.Leu125Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,794 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L125L) has been classified as Likely benign.
Frequency
Consequence
NM_022041.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAN | NM_022041.4 | c.374T>C | p.Leu125Ser | missense_variant | 3/11 | ENST00000648994.2 | |
GAN | NM_001377486.1 | c.-266T>C | 5_prime_UTR_variant | 2/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAN | ENST00000648994.2 | c.374T>C | p.Leu125Ser | missense_variant | 3/11 | NM_022041.4 | P1 | ||
GAN | ENST00000674788.1 | n.499T>C | non_coding_transcript_exon_variant | 3/3 | |||||
GAN | ENST00000648349.2 | c.*82T>C | 3_prime_UTR_variant, NMD_transcript_variant | 2/10 | |||||
GAN | ENST00000650388.1 | c.168-2289T>C | intron_variant, NMD_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461794Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727214
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Giant axonal neuropathy 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 15, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAN protein function. ClinVar contains an entry for this variant (Variation ID: 465396). This missense change has been observed in individual(s) with clinical features of giant axonal neuropathy (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 125 of the GAN protein (p.Leu125Ser). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at