Genetic Variant NM_002133.3:c.18C>G (chr22-35381191-C-G) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_002133.3(HMOX1):c.18C>G(p.Pro6Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,818 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. Synonymous variant affecting the same amino acid position (i.e. P6P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

HMOX1
NM_002133.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.73

Publications

2 publications found

Variant links:

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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
cystic fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
chronic obstructive pulmonary disease
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

HMOX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP7

Synonymous conserved (PhyloP=1.73 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMOX1	NM_002133.3	MANE Select	c.18C>G	p.Pro6Pro	synonymous	Exon 1 of 5	NP_002124.1	Q6FH11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMOX1	ENST00000216117.9	TSL:1 MANE Select	c.18C>G	p.Pro6Pro	synonymous	Exon 1 of 5	ENSP00000216117.8	P09601
HMOX1	ENST00000679074.1		c.18C>G	p.Pro6Pro	synonymous	Exon 1 of 4	ENSP00000503459.1	A0A7I2V3I1
HMOX1	ENST00000412893.5	TSL:3	c.18C>G	p.Pro6Pro	synonymous	Exon 2 of 4	ENSP00000413316.1	B1AHA8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000691

AC:

AN:

144614

AF XY:

0.0000126

show subpopulations

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:

AN:

1394818

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689324

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32224

American (AMR)

AF:

0.0000273

AC:

AN:

36578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25234

East Asian (EAS)

AF:

0.00

AC:

AN:

36608

South Asian (SAS)

AF:

0.00

AC:

AN:

79984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1084532

Other (OTH)

AF:

0.00

AC:

AN:

58256

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

9.7

(source)

DANN

Benign

0.84

PhyloP100

1.7

PromoterAI

-0.022

Neutral

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over