1-43390003-G-A

Variant names:

• chr1-43390003-G-A
• rs1648078377
• NM_001365999.1:c.27+8G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001365999.1(SZT2):​c.27+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SZT2 NM_001365999.1 splice_region, intron
• Scores: Splicing: ADA: 0.0008424
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.22
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-43390003-G-A is Benign according to our data. Variant chr1-43390003-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2828552.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SZT2	NM_001365999.1	c.27+8G>A		splice_region_variant, intron_variant	Intron 1 of 71	ENST00000634258.3	NP_001352928.1
MED8	NM_201542.5	c.-239C>T		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.27+8G>A		splice_region_variant, intron_variant	Intron 1 of 71	5	NM_001365999.1	ENSP00000489255.1
MED8	ENST00000372457.9	c.-239C>T		upstream_gene_variant		2	NM_201542.5	ENSP00000361535.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1234330 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 596864

African (AFR) AF: 0.00 AC: 0 AN: 24450

American (AMR) AF: 0.00 AC: 0 AN: 12912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17594

East Asian (EAS) AF: 0.00 AC: 0 AN: 28776

South Asian (SAS) AF: 0.00 AC: 0 AN: 58930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4320

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1006144

Other (OTH) AF: 0.00 AC: 0 AN: 51210

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.53
CADD	Benign	15
DANN	Uncertain	0.98
PhyloP100		1.2
PromoterAI		0.049	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00084
dbscSNV1_RF	Benign	0.10
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: rs1648078377; hg19: chr1-43855674;