rs2269533

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr22-35390189-A-C
• chr22-35390189-A-G
• chr22-35390189-A-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002133.3(HMOX1):​c.736+226A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 417,718 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: HMOX1 NM_002133.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).

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>C		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>C		intron	N/A	ENSP00000216117.8
	HMOX1	ENST00000494998.1	TSL:2	n.463A>C		non_coding_transcript_exon	Exon 2 of 2
	HMOX1	ENST00000679074.1		c.636+3013A>C		intron	N/A	ENSP00000503459.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000958 AC: 4 AN: 417718 Hom.: 0 Cov.: 2 AF XY: 0.0000135 AC XY: 3 AN XY: 221654

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 12108

American (AMR) AF: 0.0000490 AC: 1 AN: 20398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13068

East Asian (EAS) AF: 0.00 AC: 0 AN: 27944

South Asian (SAS) AF: 0.00 AC: 0 AN: 46958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1780

European-Non Finnish (NFE) AF: 0.0000122 AC: 3 AN: 246594

Other (OTH) AF: 0.00 AC: 0 AN: 23756

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.92
DANN	Benign	0.35
PhyloP100		-1.4

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;