1-43451268-A-C

Position:

• chr1-43451268-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.47

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 -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/exons	MANE	UniProt
HYI	NM_001190880.3	c.804T>G	p.Asp268Glu	missense_variant	8/8	ENST00000372430.9
SZT2	NM_001365999.1	c.*788A>C		3_prime_UTR_variant	72/72	ENST00000634258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HYI	ENST00000372430.9	c.804T>G	p.Asp268Glu	missense_variant	8/8	1	NM_001190880.3	P1
SZT2	ENST00000634258.3	c.*788A>C		3_prime_UTR_variant	72/72	5	NM_001365999.1	P1

Frequencies

GnomAD3 genomes AF: 0.00713 AC: 1085 AN: 152076 Hom.: 10 Cov.: 32

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.: 6 AF XY: 0.00144 AC XY: 195 AN XY: 135702

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.: 17 Cov.: 33 AF XY: 0.000598 AC XY: 435 AN XY: 727220

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.: 10 Cov.: 32 AF XY: 0.00736 AC XY: 548 AN XY: 74424

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.: 4

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

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 31, 2017	- -

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;.
MutationTaster	Benign	1.0	N;N;N;N;D;D
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

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

Other links and lift over

dbSNP: rs62620015; hg19: chr1-43916939;