chr1-43389975-T-G

Variant names:

• chr1-43389975-T-G
• rs1484505234
• NM_001365999.1:c.7T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365999.1(SZT2):​c.7T>G​(p.Ser3Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000032 in 1,251,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. S3L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: SZT2 NM_001365999.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93
• Publications: 0 publications found

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]

MED8 (HGNC:19971): (mediator complex subunit 8) This gene encodes a protein component of the mediator complex, which aids in transcriptional activation through interaction with RNA polymerase II and gene-specific transcription factors. The encoded protein may also function in ubiquitin ligation and protein degradation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10111603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.7T>G	p.Ser3Ala	missense_variant	Exon 1 of 72	ENST00000634258.3	NP_001352928.1
MED8	NM_201542.5	c.-211A>C		upstream_gene_variant		ENST00000372457.9	NP_963836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3	c.7T>G	p.Ser3Ala	missense_variant	Exon 1 of 72	5	NM_001365999.1	ENSP00000489255.1
MED8	ENST00000372457.9	c.-211A>C		upstream_gene_variant		2	NM_201542.5	ENSP00000361535.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000320 AC: 4 AN: 1251850 Hom.: 0 Cov.: 34 AF XY: 0.00000165 AC XY: 1 AN XY: 607424

African (AFR) AF: 0.00 AC: 0 AN: 25428

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17940

East Asian (EAS) AF: 0.00 AC: 0 AN: 29802

South Asian (SAS) AF: 0.00 AC: 0 AN: 61874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4892

European-Non Finnish (NFE) AF: 0.00000395 AC: 4 AN: 1013202

Other (OTH) AF: 0.00 AC: 0 AN: 51896

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 3 of the SZT2 protein (p.Ser3Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SZT2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.13	.;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.0065
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.48	T;T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.66	N;N;N
PhyloP100		1.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.5	N;.;N
REVEL	Benign	0.081
Sift	Benign	0.082	T;.;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.29
MutPred		0.26		Loss of phosphorylation at S3 (P = 0.0032);Loss of phosphorylation at S3 (P = 0.0032);Loss of phosphorylation at S3 (P = 0.0032);
MVP		0.15
MPC		0.44
ClinPred		0.29	T
GERP RS		4.3
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.11
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs1484505234; hg19: chr1-43855646;