22-35390189-A-G

Variant names:

• chr22-35390189-A-G
• rs2269533
• NM_002133.3:c.736+226A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002133.3(HMOX1):​c.736+226A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 568,774 control chromosomes in the GnomAD database, including 62,710 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.49 (19128 hom., cov: 32)
  • Exomes 𝑓: 0.45 (43582 hom.)
• Consequence: HMOX1 NM_002133.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.655 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002133.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMOX1	NM_002133.3	MANE Select	c.736+226A>G		intron	N/A	NP_002124.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMOX1	ENST00000216117.9	TSL:1 MANE Select	c.736+226A>G		intron	N/A	ENSP00000216117.8
	HMOX1	ENST00000679074.1		c.636+3013A>G		intron	N/A	ENSP00000503459.1
	HMOX1	ENST00000678411.1		c.343+226A>G		intron	N/A	ENSP00000503526.1

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74305 AN: 151792 Hom.: 19108 Cov.: 32

Gnomad AFR AF: 0.662

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.471

GnomAD4 exome AF: 0.451 AC: 188185 AN: 416864 Hom.: 43582 Cov.: 2 AF XY: 0.456 AC XY: 100958 AN XY: 221246

African (AFR) AF: 0.664 AC: 8026 AN: 12094

American (AMR) AF: 0.304 AC: 6196 AN: 20362

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 5540 AN: 13028

East Asian (EAS) AF: 0.530 AC: 14760 AN: 27874

South Asian (SAS) AF: 0.531 AC: 24949 AN: 46944

European-Finnish (FIN) AF: 0.430 AC: 10760 AN: 25040

Middle Eastern (MID) AF: 0.452 AC: 802 AN: 1774

European-Non Finnish (NFE) AF: 0.432 AC: 106391 AN: 246056

Other (OTH) AF: 0.454 AC: 10761 AN: 23692

GnomAD4 genome AF: 0.490 AC: 74370 AN: 151910 Hom.: 19128 Cov.: 32 AF XY: 0.488 AC XY: 36228 AN XY: 74230

African (AFR) AF: 0.662 AC: 27435 AN: 41448

American (AMR) AF: 0.345 AC: 5266 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1425 AN: 3468

East Asian (EAS) AF: 0.532 AC: 2738 AN: 5150

South Asian (SAS) AF: 0.534 AC: 2572 AN: 4816

European-Finnish (FIN) AF: 0.427 AC: 4507 AN: 10560

Middle Eastern (MID) AF: 0.459 AC: 134 AN: 292

European-Non Finnish (NFE) AF: 0.427 AC: 28974 AN: 67910

Other (OTH) AF: 0.469 AC: 992 AN: 2114

Alfa AF: 0.449 Hom.: 29042

Bravo AF: 0.489

Asia WGS AF: 0.566 AC: 1973 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.36
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2269533; hg19: chr22-35786182;