rs760752847

chr6-85572305-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_153816.6(SNX14):c.331C>T(p.Arg111Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000753 in 1,460,926 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SNX14 NM_153816.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.48

Genes affected

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-85572305-G-A is Pathogenic according to our data. Variant chr6-85572305-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 522726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNX14	NM_153816.6	c.331C>T	p.Arg111Ter	stop_gained	3/29	ENST00000314673.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNX14	ENST00000314673.8	c.331C>T	p.Arg111Ter	stop_gained	3/29	1	NM_153816.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251020 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135710

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460926 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726792

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 20 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The homozygous p.Arg111Ter variant in SNX14 was identified by our study in two siblings with spinocerebellar ataxia. The p.Arg111Ter variant in SNX14 has been previously reported in one individual with autosomal recessive spinocerebellar ataxia 20 (PMID: 34540776) but has been identified in 0.01% (2/18382) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs760752847). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This individual (PMID: 34540776) and the individual identified by our study were homozygotes, which increases the likelihood that the p.Arg111Ter variant in SNX14 is pathogenic. This variant has also been reported in ClinVar (Variation ID: 522726) and has been interpreted as pathogenic by the Genomic Research Center, Shahid Beheshti University of Medical Sciences. This nonsense variant leads to a premature termination codon at position 111, which is predicted to lead to a truncated or absent protein. Loss of function of the SNX14 gene is an established disease mechanism in autosomal recessive spinocerebellar ataxia 20. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive spinocerebellar ataxia 20. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.47
GERP RS		3.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs760752847; hg19: chr6-86282023;