chr1-43451427-C-G

Position:

• chr1-43451427-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The ENST00000372432.5(HYI):​c.742+1G>C variant causes a splice donor 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 ENST00000372432.5 splice_donor
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.82

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]

ACMG classification

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 0.15591398 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/exons	MANE	UniProt
HYI	NM_001190880.3	c.743G>C	p.Cys248Ser	missense_variant	7/8	ENST00000372430.9
SZT2	NM_001365999.1	c.*947C>G		3_prime_UTR_variant	72/72	ENST00000634258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HYI	ENST00000372430.9	c.743G>C	p.Cys248Ser	missense_variant	7/8	1	NM_001190880.3	P1
SZT2	ENST00000634258.3	c.*947C>G		3_prime_UTR_variant	72/72	5	NM_001365999.1	P1

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3789 AN: 152206 Hom.: 157 Cov.: 32

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.: 77 AF XY: 0.00457 AC XY: 619 AN XY: 135518

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.: 33 AF XY: 0.00213 AC XY: 1547 AN XY: 726858

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.: 32 AF XY: 0.0242 AC XY: 1805 AN XY: 74494

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.: 6

Bravo AF: 0.0289

ESP6500AA AF: 0.0856 AC: 377

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00810 AC: 984

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	32
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	D
LIST_S2	Uncertain	0.96	D;D;D
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	4.2	H;.;.
MutationTaster	Benign	2.1e-8	P;P;P;P;P;P;P
PrimateAI	Benign	0.47	T
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	T
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

Other links and lift over

dbSNP: rs79439514; hg19: chr1-43917098;