chr22-35381194-C-G

Variant names:

• chr22-35381194-C-G
• rs1483623337
• NM_002133.3:c.21C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002133.3(HMOX1):​c.21C>G​(p.Asp7Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,395,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D7H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: HMOX1 NM_002133.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10504672).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMOX1	NM_002133.3	c.21C>G	p.Asp7Glu	missense_variant, splice_region_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.21C>G	p.Asp7Glu	missense_variant, splice_region_variant	Exon 1 of 5	1	NM_002133.3	ENSP00000216117.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000690 AC: 1 AN: 144850 AF XY: 0.0000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000394

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1395160 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689538

African (AFR) AF: 0.00 AC: 0 AN: 32246

American (AMR) AF: 0.0000273 AC: 1 AN: 36622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25242

East Asian (EAS) AF: 0.00 AC: 0 AN: 36650

South Asian (SAS) AF: 0.00 AC: 0 AN: 80026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084670

Other (OTH) AF: 0.00 AC: 0 AN: 58268

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with HMOX1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 7 of the HMOX1 protein (p.Asp7Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Benign	0.18	.;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	.;N
PhyloP100		1.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.070	N;N
REVEL	Benign	0.090
Sift	Benign	0.39	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	.;B
Vest4		0.15
MutPred		0.092		Gain of solvent accessibility (P = 0.1014);Gain of solvent accessibility (P = 0.1014);
MVP		0.29
MPC		0.051
ClinPred		0.047	T
GERP RS		3.4
PromoterAI		-0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.095
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1483623337; hg19: chr22-35777187;