6-85507264-ACAATGTC-A

Position:

• chr6-85507264-ACAATGTC-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_153816.6(SNX14):​c.2764_2770del​(p.Asp922Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SNX14 NM_153816.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.43

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0271 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-85507264-ACAATGTC-A is Pathogenic according to our data. Variant chr6-85507264-ACAATGTC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 419155.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNX14	NM_153816.6	c.2764_2770del	p.Asp922Ter	frameshift_variant	28/29	ENST00000314673.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNX14	ENST00000314673.8	c.2764_2770del	p.Asp922Ter	frameshift_variant	28/29	1	NM_153816.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249268 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459096 Hom.: 0 AF XY: 0.00000551 AC XY: 4 AN XY: 725764

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000468

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2017

The c.2764_2770delGACATTG deletion in the SNX14 gene has been reported previously in thehomozygous state in association with SNX14-related disorder (Akizu et al., 2015). Thec.2764_2770delGACATTG variant changes codon Aspartic acid 922 to a premature Stop codon, denotedp.Asp922Ter. This deletion is predicted to cause loss of normal protein function through proteintruncation. The c.2764_2770delGACATTG deletion was not observed in approximately 6500 individualsof European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is nota common benign variant in these populations. We interpret c.2764_2770delGACATTG as a pathogenic variant. -

Autosomal recessive spinocerebellar ataxia 20 Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 02, 2023

The homozygous p.Leu921_Asp922insTer variant in SNX14 was identified by our study in one individual with spinocerebellar ataxia. The p.Leu921_Asp922insTer variant in SNX14 has been previously reported in 2 affected siblings from one family with autosomal recessive spinocerebellar ataxia 20 (PMID: 25848753) but has been identified in 0.00003% (1/30084) of South Asian chromosomes by the by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1064793681). 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. These two affected siblings were homozygotes (PMID: 25848753) and the individual identified by our study was a homozygote, which increases the likelihood that the p.Leu921_Asp922insTer variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 419155) and has been interpreted as pathogenic by GeneDx. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 922 and leads to a premature termination codon 1 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the SNX14 gene is an established disease mechanism in autosomal recessive spinocerebellar ataxia 20. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PM2_Supporting, PM3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064793681; hg19: chr6-86216982;