chr22-35381202-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_002133.3(HMOX1):c.23+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000375 in 1,546,688 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 1 hom. )
Consequence
HMOX1
NM_002133.3 splice_donor_region, intron
NM_002133.3 splice_donor_region, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.658
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00021 (32/152332) while in subpopulation AFR AF= 0.000746 (31/41572). AF 95% confidence interval is 0.000539. There are 0 homozygotes in gnomad4. There are 12 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.23+6C>T | splice_donor_region_variant, intron_variant | ENST00000216117.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HMOX1 | ENST00000216117.9 | c.23+6C>T | splice_donor_region_variant, intron_variant | 1 | NM_002133.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000210 AC: 32AN: 152214Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000418 AC: 6AN: 143414Hom.: 0 AF XY: 0.0000254 AC XY: 2AN XY: 78806
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GnomAD4 exome AF: 0.0000186 AC: 26AN: 1394356Hom.: 1 Cov.: 31 AF XY: 0.0000145 AC XY: 10AN XY: 689104
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change falls in intron 1 of the HMOX1 gene. It does not directly change the encoded amino acid sequence of the HMOX1 protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with HMOX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1481127). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at