rs368593287

Variant names:

• chr1-43451281-C-A
• rs368593287
• NM_001190880.3:c.791G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-43451281-C-A
• chr1-43451281-C-T

Variant summary

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

The NM_001190880.3(HYI):​c.791G>T​(p.Arg264Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R264C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HYI NM_001190880.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.232
• Publications: 0 publications found

Genes affected

HYI (HGNC:26948): (hydroxypyruvate isomerase (putative)) This gene encodes a putative hydroxypyruvate isomerase, which likely catalyzes the conversion of hydroxypyruvate to 2-hydroxy-3-oxopropanoate, and may be involved in carbohydrate transport and metabolism. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

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]

SZT2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 18

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, PanelApp Australia
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190880.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYI	NM_001190880.3	MANE Select	c.791G>T	p.Arg264Leu	missense	Exon 8 of 8	NP_001177809.1	Q5T013-1
	SZT2	NM_001365999.1	MANE Select	c.*801C>A		3_prime_UTR	Exon 72 of 72	NP_001352928.1	Q5T011-1
	HYI	NM_001330526.2		c.866G>T	p.Arg289Leu	missense	Exon 9 of 9	NP_001317455.1	F6UJY1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYI	ENST00000372430.9	TSL:1 MANE Select	c.791G>T	p.Arg264Leu	missense	Exon 8 of 8	ENSP00000361507.4	Q5T013-1
	SZT2	ENST00000634258.3	TSL:5 MANE Select	c.*801C>A		3_prime_UTR	Exon 72 of 72	ENSP00000489255.1	Q5T011-1
	HYI	ENST00000372432.5	TSL:1	c.*29G>T		3_prime_UTR	Exon 8 of 8	ENSP00000361509.1	Q5T013-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461778 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.23
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.084
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.055	T
Polyphen		0.34	B
Vest4		0.56
MutPred		0.51		Loss of MoRF binding (P = 0.0218)
MVP		0.58
MPC		0.082
ClinPred		0.93	D
GERP RS		2.8
Varity_R		0.15
gMVP		0.79
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs368593287; hg19: chr1-43916952;