1-43451427-C-G

Variant names:

• chr1-43451427-C-G
• rs79439514
• NM_001190880.3:c.743G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_001243526.2(HYI):​c.817+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,613,346 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (158 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (158 hom.)
• Consequence: HYI NM_001243526.2 splice_donor, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.82
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.14285715 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.4, offset of 18, new splice context is: gagGTgagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 1-43451427-C-G is Benign according to our data. Variant chr1-43451427-C-G is described in ClinVar as Benign. ClinVar VariationId is 783286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0845 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243526.2. 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.743G>C	p.Cys248Ser	missense	Exon 7 of 8	NP_001177809.1	Q5T013-1
	SZT2	NM_001365999.1	MANE Select	c.*947C>G		3_prime_UTR	Exon 72 of 72	NP_001352928.1	Q5T011-1
	HYI	NM_001330526.2		c.818G>C	p.Cys273Ser	missense	Exon 8 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.743G>C	p.Cys248Ser	missense	Exon 7 of 8	ENSP00000361507.4	Q5T013-1
	SZT2	ENST00000634258.3	TSL:5 MANE Select	c.*947C>G		3_prime_UTR	Exon 72 of 72	ENSP00000489255.1	Q5T011-1
	HYI	ENST00000372432.5	TSL:1	c.742+1G>C		splice_donor intron	N/A	ENSP00000361509.1	Q5T013-3

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3789 AN: 152206 Hom.: 157 Cov.: 32

Gnomad AFR AF: 0.0869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00643 AC: 1612 AN: 250526 AF XY: 0.00457

Gnomad AFR exome AF: 0.0870

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00249 AC: 3637 AN: 1461022 Hom.: 158 Cov.: 33 AF XY: 0.00213 AC XY: 1547 AN XY: 726858

African (AFR) AF: 0.0890 AC: 2979 AN: 33480

American (AMR) AF: 0.00490 AC: 219 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52566

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.0000809 AC: 90 AN: 1112000

Other (OTH) AF: 0.00523 AC: 316 AN: 60390

GnomAD4 genome AF: 0.0249 AC: 3798 AN: 152324 Hom.: 158 Cov.: 32 AF XY: 0.0242 AC XY: 1805 AN XY: 74494

African (AFR) AF: 0.0869 AC: 3612 AN: 41566

American (AMR) AF: 0.00862 AC: 132 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68028

Other (OTH) AF: 0.0133 AC: 28 AN: 2112

Alfa AF: 0.00136 Hom.: 6

Bravo AF: 0.0289

ESP6500AA AF: 0.0856 AC: 377

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00810 AC: 984

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.8
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.97	D
Vest4		0.90
MutPred		0.75		Gain of disorder (P = 0.0088)
MVP		0.50
MPC		0.38
ClinPred		0.12	T
GERP RS		5.5
Varity_R		0.82
gMVP		0.89
Mutation Taster		=49/51	polymorphism (auto)

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: rs79439514; hg19: chr1-43917098;