Variant chr6-85507264-ACAATGTC-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_153816.6(SNX14):c.2764_2770delGACATTG(p.Asp922fs) 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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 8.43

Variant links:

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]

SNX14 links:

ENSG00000271793 (HGNC:):

ENSG00000271793 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
SNX14	NM_153816.6 link	c.2764_2770delGACATTG	p.Asp922fs	frameshift_variant	Exon 28 of 29	ENST00000314673.8	NP_722523.1	Q9Y5W7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SNX14	ENST00000314673.8 link	c.2764_2770delGACATTG	p.Asp922fs	frameshift_variant	Exon 28 of 29	1	NM_153816.6	ENSP00000313121.3	Q9Y5W7-1
ENSG00000271793	ENST00000682083.1 link	n.2674_2680delGACATTG		non_coding_transcript_exon_variant	Exon 39 of 40			ENSP00000506859.1
ENSG00000271793	ENST00000682083.1 link	n.2674_2680delGACATTG		3_prime_UTR_variant	Exon 39 of 40			ENSP00000506859.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249268

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134796

show subpopulations

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:

AN:

1459096

Hom.:

AF XY:

0.00000551

AC XY:

AN XY:

725764

show subpopulations

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.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

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‚Äôs 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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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