chr1-43451427-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.82

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYI	NM_001190880.3 link	c.743G>C	p.Cys248Ser	missense_variant	Exon 7 of 8	ENST00000372430.9	NP_001177809.1	Q5T013-1
SZT2	NM_001365999.1 link	c.*947C>G		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.743G>C	p.Cys248Ser	missense_variant	Exon 7 of 8	1	NM_001190880.3	ENSP00000361507.4		Q5T013-1J9JIE9
SZT2	ENST00000634258.3 link	c.*947C>G		3_prime_UTR_variant	Exon 72 of 72	5	NM_001365999.1	ENSP00000489255.1		Q5T011-1

Frequencies

GnomAD3 genomes

AF:

0.0249

AC:

3789

AN:

152206

Hom.:

157

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00643

AC:

1612

AN:

250526

Hom.:

AF XY:

0.00457

AC XY:

619

AN XY:

135518

show subpopulations

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 SAS exome

AF:

0.0000653

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.:

AF XY:

0.00213

AC XY:

1547

AN XY:

726858

show subpopulations

Gnomad4 AFR exome

AF:

0.0890

Gnomad4 AMR exome

AF:

0.00490

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000809

Gnomad4 OTH exome

AF:

0.00523

GnomAD4 genome

AF:

0.0249

AC:

3798

AN:

152324

Hom.:

158

Cov.:

AF XY:

0.0242

AC XY:

1805

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0869

Gnomad4 AMR

AF:

0.00862

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.0133

Alfa

AF:

0.00136

Hom.:

Bravo

AF:

0.0289

ESP6500AA

AF:

0.0856

AC:

377

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00810

AC:

984

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;T;T

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Pathogenic

4.2

H;.;.

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-6.3

D;.;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

0.97

D;.;.

Vest4

0.90

MutPred

0.75

Gain of disorder (P = 0.0088);.;Gain of disorder (P = 0.0088);

MVP

0.50

MPC

0.38

ClinPred

0.12

GERP RS

5.5

Varity_R

0.82

gMVP

0.89

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

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