Genetic Variant SZT2:c.*1450C>T (chr1-43451930-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PP3_ModerateBP6_ModerateBS1BS2

The NM_001190880.3(HYI):c.505+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00262 in 1,612,544 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0071 ( 16 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 44 hom. )

Consequence

HYI
NM_001190880.3 splice_region, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.86

Publications

2 publications found

Variant links:

Genes affected

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:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BP6

Variant 1-43451930-C-T is Benign according to our data. Variant chr1-43451930-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 445670.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00706 (1074/152206) while in subpopulation SAS AF = 0.023 (111/4818). AF 95% confidence interval is 0.0196. There are 16 homozygotes in GnomAd4. There are 525 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SZT2	NM_001365999.1	MANE Select	c.*1450C>T	3_prime_UTR	Exon 72 of 72	NP_001352928.1
HYI	NM_001190880.3	MANE Select	c.505+5G>A	splice_region intron	N/A	NP_001177809.1
SZT2	NM_015284.4		c.*1450C>T	3_prime_UTR	Exon 71 of 71	NP_056099.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SZT2	ENST00000634258.3	TSL:5 MANE Select	c.*1450C>T	3_prime_UTR	Exon 72 of 72	ENSP00000489255.1
HYI	ENST00000372430.9	TSL:1 MANE Select	c.505+5G>A	splice_region intron	N/A	ENSP00000361507.4
HYI	ENST00000372432.5	TSL:1	c.505+5G>A	splice_region intron	N/A	ENSP00000361509.1

Frequencies

GnomAD3 genomes

AF:

0.00699

AC:

1063

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0199

Gnomad SAS

AF:

0.0230

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00537

AC:

1346

AN:

250428

AF XY:

0.00565

show subpopulations

Gnomad AFR exome

AF:

0.0209

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.000401

Gnomad EAS exome

AF:

0.0231

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000212

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00216

AC:

3152

AN:

1460338

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

1850

AN XY:

726214

show subpopulations

African (AFR)

AF:

0.0189

AC:

632

AN:

33468

American (AMR)

AF:

0.00132

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.000652

AC:

AN:

26074

East Asian (EAS)

AF:

0.0152

AC:

603

AN:

39656

South Asian (SAS)

AF:

0.0164

AC:

1417

AN:

86198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000141

AC:

157

AN:

1110822

Other (OTH)

AF:

0.00416

AC:

251

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

197

395

592

790

987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.00706

AC:

1074

AN:

152206

Hom.:

Cov.:

AF XY:

0.00706

AC XY:

525

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0191

AC:

794

AN:

41532

American (AMR)

AF:

0.00301

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0200

AC:

103

AN:

5160

South Asian (SAS)

AF:

0.0230

AC:

111

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67998

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

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:

0.0441

Hom.:

2355

Bravo

AF:

0.00740

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

5.9

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.29

Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over