22-35381161-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_002133.3(HMOX1):c.-13C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,542,340 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (1 hom.)
• Consequence: HMOX1 NM_002133.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.124

Genes affected

HMOX1 (HGNC:5013): (heme oxygenase 1) Heme oxygenase, an essential enzyme in heme catabolism, cleaves heme to form biliverdin, which is subsequently converted to bilirubin by biliverdin reductase, and carbon monoxide, a putative neurotransmitter. Heme oxygenase activity is induced by its substrate heme and by various nonheme substances. Heme oxygenase occurs as 2 isozymes, an inducible heme oxygenase-1 and a constitutive heme oxygenase-2. HMOX1 and HMOX2 belong to the heme oxygenase family. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00104 (159/152364) while in subpopulation NFE AF= 0.00184 (125/68038). AF 95% confidence interval is 0.00157. There are 1 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMOX1	NM_002133.3	c.-13C>T		5_prime_UTR_variant	1/5	ENST00000216117.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMOX1	ENST00000216117.9	c.-13C>T		5_prime_UTR_variant	1/5	1	NM_002133.3	P1

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 159 AN: 152246 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000835 AC: 115 AN: 137772 Hom.: 0 AF XY: 0.000939 AC XY: 71 AN XY: 75626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000395

Gnomad FIN exome AF: 0.00137

Gnomad NFE exome AF: 0.00158

Gnomad OTH exome AF: 0.000721

GnomAD4 exome AF: 0.00166 AC: 2306 AN: 1389976 Hom.: 1 Cov.: 31 AF XY: 0.00160 AC XY: 1101 AN XY: 686652

Gnomad4 AFR exome AF: 0.000188

Gnomad4 AMR exome AF: 0.000472

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000364

Gnomad4 FIN exome AF: 0.00247

Gnomad4 NFE exome AF: 0.00195

Gnomad4 OTH exome AF: 0.000981

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152364 Hom.: 1 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74506

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.000846

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	9.8
Dann	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs9282701; hg19: chr22-35777154;