rs587777099

chr1-43430069-ACTT-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_001365999.1(SZT2):c.4373_4375del(p.Phe1458del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000274 in 1,461,894 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: SZT2 NM_001365999.1 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 6.79

Genes affected

SZT2 (HGNC:29040): (SZT2 subunit of KICSTOR complex) The protein encoded by this gene is expressed in the brain, predominantly in the parietal and frontal cortex as well as in dorsal root ganglia. It is localized to the peroxisome, and is implicated in resistance to oxidative stress. It likely functions by increasing superoxide dismutase (SOD) activity, but itself has no direct SOD activity. Studies in mice show that this gene confers low seizure threshold, and may also enhance epileptogenesis. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001365999.1. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-43430069-ACTT-A is Pathogenic according to our data. Variant chr1-43430069-ACTT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97056.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SZT2	NM_001365999.1	c.4373_4375del	p.Phe1458del	inframe_deletion	30/72	ENST00000634258.3
SZT2	NM_015284.4	c.4202_4204del	p.Phe1401del	inframe_deletion	29/71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SZT2	ENST00000634258.3	c.4373_4375del	p.Phe1458del	inframe_deletion	30/72	5	NM_001365999.1	P1
SZT2	ENST00000562955.2	c.4202_4204del	p.Phe1401del	inframe_deletion	29/71	5
SZT2	ENST00000478140.1	n.234_236del		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461894 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of one amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23932106, 24784157, 27248490, 24324832, 30818181, 28556953, 29696782) -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Sep 05, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 27, 2021	This variant, c.4202_4204del, results in the deletion of 1 amino acid(s) of the SZT2 protein (p.Phe1401del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of SZT2-related conditions (PMID: 24324832). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 97056). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs587777099; hg19: chr1-43895740;