1-43430742-G-T

Variant names:

• chr1-43430742-G-T
• rs143935839
• NM_001365999.1:c.4727G>T

Variant summary

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

The NM_001365999.1(SZT2):​c.4727G>T​(p.Arg1576Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1576H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SZT2 NM_001365999.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.84

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=0.29798943).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.4727G>T	p.Arg1576Leu	missense_variant	Exon 32 of 72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4	c.4556G>T	p.Arg1519Leu	missense_variant	Exon 31 of 71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.4727G>T	p.Arg1576Leu	missense_variant	Exon 32 of 72	5	NM_001365999.1	ENSP00000489255.1
SZT2	ENST00000562955.2	c.4556G>T	p.Arg1519Leu	missense_variant	Exon 31 of 71	5		ENSP00000457168.1
SZT2	ENST00000478140.1	n.*45G>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249424 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134970

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460362 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726520

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Benign	0.012
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.8	.;D
Sift	Uncertain	0.013	.;D
Sift4G	Uncertain	0.020	D;D
Polyphen		0.21	.;B
Vest4		0.52
MutPred		0.37		.;Loss of sheet (P = 0.0457);
MVP		0.37
MPC		0.35
ClinPred		0.61	D
GERP RS		3.9
Varity_R		0.11
gMVP		0.49

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: rs143935839; hg19: chr1-43896413;