chr1-43451268-A-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

Clinical Significance

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

Conservation

PhyloP100: -1.47

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]

HYI links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYI	NM_001190880.3 link	c.804T>G	p.Asp268Glu	missense_variant	Exon 8 of 8	ENST00000372430.9	NP_001177809.1	Q5T013-1
SZT2	NM_001365999.1 link	c.*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
HYI	ENST00000372430.9 link	c.804T>G	p.Asp268Glu	missense_variant	Exon 8 of 8	1	NM_001190880.3	ENSP00000361507.4		Q5T013-1J9JIE9
SZT2	ENST00000634258.3 link	c.*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.:

Cov.:

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

GnomAD3 exomes

AF:

0.00191

AC:

479

AN:

251006

Hom.:

AF XY:

0.00144

AC XY:

195

AN XY:

135702

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 SAS exome

AF:

0.0000327

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.:

Cov.:

AF XY:

0.000598

AC XY:

435

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0244

Gnomad4 AMR exome

AF:

0.000984

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.00162

GnomAD4 genome

AF:

0.00716

AC:

1089

AN:

152194

Hom.:

Cov.:

AF XY:

0.00736

AC XY:

548

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0248

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.000978

Hom.:

Bravo

AF:

0.00827

ESP6500AA

AF:

0.0286

AC:

126

ESP6500EA

AF:

0.000116

AC:

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

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

LIST_S2

Benign

0.68

T;T

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.43

N;.

PrimateAI

Benign

0.38

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

GERP RS

-9.3

Varity_R

0.041

gMVP

0.52

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over