1-43424314-A-T

Variant names:

• chr1-43424314-A-T
• rs754599484
• NM_001365999.1:c.2353A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001365999.1(SZT2):​c.2353A>T​(p.Ser785Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,445,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S785G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SZT2 NM_001365999.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.68

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32266372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.2353A>T	p.Ser785Cys	missense_variant	Exon 16 of 72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4	c.2353A>T	p.Ser785Cys	missense_variant	Exon 16 of 71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.2353A>T	p.Ser785Cys	missense_variant	Exon 16 of 72	5	NM_001365999.1	ENSP00000489255.1
SZT2	ENST00000562955.2	c.2353A>T	p.Ser785Cys	missense_variant	Exon 16 of 71	5		ENSP00000457168.1
SZT2	ENST00000470139.1	n.1084A>T		non_coding_transcript_exon_variant	Exon 7 of 18	2		ENSP00000492726.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445910 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719692

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2353A>T (p.S785C) alteration is located in exon 16 (coding exon 16) of the SZT2 gene. This alteration results from a A to T substitution at nucleotide position 2353, causing the serine (S) at amino acid position 785 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.0023	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.088	T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.32	T;T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.5	.;N
Sift	Benign	0.071	.;T
Sift4G	Uncertain	0.010	D;D
Vest4		0.42
MVP		0.63
MPC		1.4
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.58

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: rs754599484; hg19: chr1-43889985;