chr22-35381161-C-T

Variant names:

• chr22-35381161-C-T
• rs9282701
• NM_002133.3:c.-13C>T

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 2 publications found

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]

HMOX1 Gene-Disease associations (from GenCC):

• heme oxygenase 1 deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• chronic obstructive pulmonary disease

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMOX1	NM_002133.3	c.-13C>T		5_prime_UTR_variant	Exon 1 of 5	ENST00000216117.9	NP_002124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMOX1	ENST00000216117.9	c.-13C>T		5_prime_UTR_variant	Exon 1 of 5	1	NM_002133.3	ENSP00000216117.8

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

GnomAD2 exomes AF: 0.000835 AC: 115 AN: 137772 AF XY: 0.000939

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 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

African (AFR) AF: 0.000188 AC: 6 AN: 31990

American (AMR) AF: 0.000472 AC: 17 AN: 36040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25160

East Asian (EAS) AF: 0.00 AC: 0 AN: 36308

South Asian (SAS) AF: 0.000364 AC: 29 AN: 79574

European-Finnish (FIN) AF: 0.00247 AC: 87 AN: 35200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00195 AC: 2110 AN: 1081936

Other (OTH) AF: 0.000981 AC: 57 AN: 58098

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

African (AFR) AF: 0.000216 AC: 9 AN: 41584

American (AMR) AF: 0.000392 AC: 6 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 68038

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00175 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

Jul 09, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.8
DANN	Benign	0.94
PhyloP100		-0.12
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=296/4	polymorphism

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

Other links and lift over

dbSNP: rs9282701; hg19: chr22-35777154;