1-43451268-A-C

Variant names:

• chr1-43451268-A-C
• rs62620015
• NM_001190880.3:c.804T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001190880.3(HYI):​c.804T>G​(p.Asp268Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,613,994 control chromosomes in the GnomAD database, including 27 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (17 hom.)
• Consequence: HYI NM_001190880.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.47
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033923686).
• BP6: Variant 1-43451268-A-C is Benign according to our data. Variant chr1-43451268-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00716 (1089/152194) while in subpopulation AFR AF = 0.0248 (1032/41534). AF 95% confidence interval is 0.0236. There are 10 homozygotes in GnomAd4. There are 548 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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.804T>G	p.Asp268Glu	missense	Exon 8 of 8	NP_001177809.1	Q5T013-1
	SZT2	NM_001365999.1	MANE Select	c.*788A>C		3_prime_UTR	Exon 72 of 72	NP_001352928.1	Q5T011-1
	HYI	NM_001330526.2		c.879T>G	p.Asp293Glu	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.804T>G	p.Asp268Glu	missense	Exon 8 of 8	ENSP00000361507.4	Q5T013-1
	SZT2	ENST00000634258.3	TSL:5 MANE Select	c.*788A>C		3_prime_UTR	Exon 72 of 72	ENSP00000489255.1	Q5T011-1
	HYI	ENST00000372432.5	TSL:1	c.*42T>G		3_prime_UTR	Exon 8 of 8	ENSP00000361509.1	Q5T013-3

Frequencies

GnomAD3 genomes AF: 0.00713 AC: 1085 AN: 152076 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00191 AC: 479 AN: 251006 AF XY: 0.00144

Gnomad AFR exome AF: 0.0262

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000688 AC: 1005 AN: 1461800 Hom.: 17 Cov.: 33 AF XY: 0.000598 AC XY: 435 AN XY: 727220

African (AFR) AF: 0.0244 AC: 817 AN: 33480

American (AMR) AF: 0.000984 AC: 44 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: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1112008

Other (OTH) AF: 0.00162 AC: 98 AN: 60392

GnomAD4 genome AF: 0.00716 AC: 1089 AN: 152194 Hom.: 10 Cov.: 32 AF XY: 0.00736 AC XY: 548 AN XY: 74424

African (AFR) AF: 0.0248 AC: 1032 AN: 41534

American (AMR) AF: 0.00235 AC: 36 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67974

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00256 Hom.: 11

Bravo AF: 0.00827

ESP6500AA AF: 0.0286 AC: 126

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00241 AC: 293

ClinVar

ClinVar submissions

Significance: Likely 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	Benign	0.099
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.14
DANN	Benign	0.53
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.43	N
PhyloP100		-1.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.017
Sift	Benign	0.57	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.055
MutPred		0.25		Loss of loop (P = 0.0203)
MVP		0.13
MPC		0.051
ClinPred		0.0014	T
GERP RS		-9.3
Varity_R		0.041
gMVP		0.52
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs62620015; hg19: chr1-43916939;