chr1-43389907-G-C

Variant names:

• chr1-43389907-G-C
• rs839753
• NM_001365999.1:c.-62G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001365999.1(SZT2):​c.-62G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,553,340 control chromosomes in the GnomAD database, including 327,454 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.66 (32991 hom., cov: 33)
  • Exomes 𝑓: 0.65 (294463 hom.)
• Consequence: SZT2 NM_001365999.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0970
• Publications: 14 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.-62G>C		5_prime_UTR_variant	Exon 1 of 72	ENST00000634258.3	NP_001352928.1
MED8	NM_201542.5	c.-143C>G		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.-62G>C		5_prime_UTR_variant	Exon 1 of 72	5	NM_001365999.1	ENSP00000489255.1
MED8	ENST00000372457.9	c.-143C>G		upstream_gene_variant		2	NM_201542.5	ENSP00000361535.4

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99789 AN: 152044 Hom.: 32950 Cov.: 33

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.642

Gnomad ASJ AF: 0.658

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.687

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.673

GnomAD4 exome AF: 0.646 AC: 905338 AN: 1401178 Hom.: 294463 Cov.: 39 AF XY: 0.642 AC XY: 445031 AN XY: 693260

African (AFR) AF: 0.685 AC: 21555 AN: 31454

American (AMR) AF: 0.596 AC: 23438 AN: 39346

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 15511 AN: 23444

East Asian (EAS) AF: 0.500 AC: 18173 AN: 36318

South Asian (SAS) AF: 0.496 AC: 39347 AN: 79380

European-Finnish (FIN) AF: 0.680 AC: 30734 AN: 45172

Middle Eastern (MID) AF: 0.652 AC: 3628 AN: 5562

European-Non Finnish (NFE) AF: 0.661 AC: 715409 AN: 1082390

Other (OTH) AF: 0.646 AC: 37543 AN: 58112

GnomAD4 genome AF: 0.657 AC: 99898 AN: 152162 Hom.: 32991 Cov.: 33 AF XY: 0.654 AC XY: 48618 AN XY: 74394

African (AFR) AF: 0.686 AC: 28474 AN: 41526

American (AMR) AF: 0.642 AC: 9822 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 2284 AN: 3470

East Asian (EAS) AF: 0.523 AC: 2698 AN: 5160

South Asian (SAS) AF: 0.499 AC: 2407 AN: 4822

European-Finnish (FIN) AF: 0.687 AC: 7270 AN: 10586

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44740 AN: 67986

Other (OTH) AF: 0.675 AC: 1428 AN: 2116

Alfa AF: 0.654 Hom.: 4066

Bravo AF: 0.658

Asia WGS AF: 0.518 AC: 1802 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.91
PhyloP100		-0.097
PromoterAI		-0.13	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs839753; hg19: chr1-43855578; COSMIC: COSV51941570; COSMIC: COSV51941570;