rs62620015

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

18

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.47

Publications

3 publications found
Variant links:
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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
  • genetic developmental and epileptic encephalopathy
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • undetermined early-onset epileptic encephalopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 CliVar as Likely_benign. Clinvar id is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43451268-A-C is described in CliVar as Likely_benign. Clinvar id is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43451268-A-C is described in CliVar as Likely_benign. Clinvar id is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43451268-A-C is described in CliVar as Likely_benign. Clinvar id is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43451268-A-C is described in CliVar as Likely_benign. Clinvar id is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43451268-A-C is described in CliVar as Likely_benign. Clinvar id is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43451268-A-C is described in CliVar as Likely_benign. Clinvar id is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43451268-A-C is described in CliVar as Likely_benign. Clinvar id is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43451268-A-C is described in CliVar as Likely_benign. Clinvar id is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43451268-A-C is described in CliVar as Likely_benign. Clinvar id is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43451268-A-C is described in CliVar as Likely_benign. Clinvar id is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43451268-A-C is described in CliVar as Likely_benign. Clinvar id is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43451268-A-C is described in CliVar as Likely_benign. Clinvar id is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43451268-A-C is described in CliVar as Likely_benign. Clinvar id is 445494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43451268-A-C is described in CliVar as Likely_benign. Clinvar id 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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HYINM_001190880.3 linkc.804T>G p.Asp268Glu missense_variant Exon 8 of 8 ENST00000372430.9 NP_001177809.1 Q5T013-1
SZT2NM_001365999.1 linkc.*788A>C 3_prime_UTR_variant Exon 72 of 72 ENST00000634258.3 NP_001352928.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HYIENST00000372430.9 linkc.804T>G p.Asp268Glu missense_variant Exon 8 of 8 1 NM_001190880.3 ENSP00000361507.4 Q5T013-1J9JIE9
SZT2ENST00000634258.3 linkc.*788A>C 3_prime_UTR_variant Exon 72 of 72 5 NM_001365999.1 ENSP00000489255.1 Q5T011-1

Frequencies

GnomAD3 genomes
AF:
0.00713
AC:
1085
AN:
152076
Hom.:
10
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
70
140
210
280
350
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
28
56
84
112
140
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00716
AC:
1089
AN:
152194
Hom.:
10
Cov.:
32
AF XY:
0.00736
AC XY:
548
AN XY:
74424
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.498
Heterozygous variant carriers
0
52
104
155
207
259
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Aug 31, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.074
N
LIST_S2
Benign
0.68
T;T
MetaRNN
Benign
0.0034
T;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;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

Publications

Other links and lift over

dbSNP: rs62620015; hg19: chr1-43916939; API