Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_153816.6(SNX14):c.1894+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,384,870 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (no stars).
SNX14 (HGNC:14977): (sorting nexin 14) This gene encodes a member of the sorting nexin family. Members of this family have a phox (PX) phosphoinositide binding domain and are involved in intracellular trafficking. The encoded protein also contains a regulator of G protein signaling (RGS) domain. Regulator of G protein signaling family members are regulatory molecules that act as GTPase activating proteins for G alpha subunits of heterotrimeric G proteins. Alternate splicing results in transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]
SNX14 Gene-Disease associations (from GenCC):
autosomal recessive spinocerebellar ataxia 20
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.029567054 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-85530191-C-A is Pathogenic according to our data. Variant chr6-85530191-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190317.Status of the report is no_assertion_criteria_provided, 0 stars.
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
31338
American (AMR)
AF:
0.00
AC:
0
AN:
42322
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25572
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38538
South Asian (SAS)
AF:
0.00
AC:
0
AN:
82460
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51928
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5618
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1049270
Other (OTH)
AF:
0.0000346
AC:
2
AN:
57824
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Variant confirmed as disease-causing by referring clinical team -
SNX14-related disorderPathogenic:1
Mar 06, 2024
PreventionGenetics, part of Exact Sciences
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
The SNX14 c.1894+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the homozygous state in an individual with intellectual disability, cerebellar ataxia & atrophy, hearing loss, progressively coarsening facial features & macrocephaly (Thomas et al. 2014. PubMed ID: 25439728). Functional analysis indicated that this nucleotide change resulted in an in-frame deletion of exon 19 (Thomas et al. 2014. PubMed ID: 25439728). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in SNX14 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -