Genetic Variant HMOX2:c.-41-8899G>C (chr16-4496585-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002134.4(HMOX2):c.-41-8899G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 152,084 control chromosomes in the GnomAD database, including 25,541 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 0.54 ( 25538 hom., cov: 31)

Exomes 𝑓: 0.88 ( 3 hom. )

Consequence

HMOX2
NM_002134.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.94

Publications

13 publications found

Variant links:

Genes affected

HMOX2 (HGNC:5014): (heme oxygenase 2) 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. Several alternatively spliced transcript variants encoding three different isoforms have been found for this gene. [provided by RefSeq, Oct 2013]

HMOX2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002134.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HMOX2	NM_002134.4	MANE Select	c.-41-8899G>C	intron	N/A	NP_002125.3
HMOX2	NM_001286267.2		c.121+319G>C	intron	N/A	NP_001273196.1	A0A087WT44
HMOX2	NM_001127204.2		c.-41-8899G>C	intron	N/A	NP_001120676.1	P30519-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HMOX2	ENST00000570646.6	TSL:1 MANE Select	c.-41-8899G>C	intron	N/A	ENSP00000459214.1	P30519-1
HMOX2	ENST00000964456.1		c.-2851G>C	5_prime_UTR	Exon 2 of 7	ENSP00000634515.1
HMOX2	ENST00000964458.1		c.-925G>C	5_prime_UTR	Exon 2 of 8	ENSP00000634517.1

Frequencies

GnomAD3 genomes

AF:

0.541

AC:

82147

AN:

151958

Hom.:

25530

Cov.:

show subpopulations

Gnomad AFR

AF:

0.219

Gnomad AMI

AF:

0.458

Gnomad AMR

AF:

0.549

Gnomad ASJ

AF:

0.618

Gnomad EAS

AF:

0.643

Gnomad SAS

AF:

0.540

Gnomad FIN

AF:

0.730

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.694

Gnomad OTH

AF:

0.568

GnomAD4 exome

AF:

0.875

AC:

AN:

Hom.:

Cov.:

AF XY:

0.875

AC XY:

AN XY:

show subpopulations

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

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.833

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.540

AC:

82167

AN:

152076

Hom.:

25538

Cov.:

AF XY:

0.540

AC XY:

40173

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.218

AC:

9057

AN:

41466

American (AMR)

AF:

0.550

AC:

8398

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.618

AC:

2144

AN:

3470

East Asian (EAS)

AF:

0.642

AC:

3322

AN:

5176

South Asian (SAS)

AF:

0.542

AC:

2612

AN:

4820

European-Finnish (FIN)

AF:

0.730

AC:

7710

AN:

10566

Middle Eastern (MID)

AF:

0.514

AC:

151

AN:

294

European-Non Finnish (NFE)

AF:

0.694

AC:

47167

AN:

67984

Other (OTH)

AF:

0.563

AC:

1188

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1605

3210

4816

6421

8026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

704

1408

2112

2816

3520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.614

Hom.:

3918

Bravo

AF:

0.515

Asia WGS

AF:

0.494

AC:

1720

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

8.0

(source)

DANN

Benign

0.67

PhyloP100

1.9

PromoterAI

-0.022

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

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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