rs8139532

Variant names:

• chr22-35383575-G-A
• rs8139532
• NM_002133.3:c.144+349G>A

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_002133.3(HMOX1):c.144+349G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.154 (AC=23,357) in the gnomAD database across 152,146 control chromosomes, including 3,755 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.407. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (3755 hom., cov: 31)
• Consequence: HMOX1 NM_002133.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.612
• Publications: 3 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: Orphanet, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• chronic obstructive pulmonary disease

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4067 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002133.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	HMOX1 NM_002133.3	MANE Select	c.144+349G>A	intron	Intron 2 of 4	Prot: NP_002124.1 UniProt:

HMOX1 NM_002133.3

MANE Select

HGVSc / HGVSpc.144+349G>A

Exon rankIntron 2 of 4

intron

Prot: NP_002124.1UniProt: P09601Q6FH11

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	HMOX1 ENST00000216117.9	TSL:1MANE Select	c.144+349G>A	intron	Intron 2 of 4	Prot: ENSP00000216117.8 UniProt:
	HMOX1 ENST00000679074.1		c.144+349G>A	intron	Intron 2 of 3	Prot: ENSP00000503459.1 UniProt:
	HMOX1 ENST00000412893.5	TSL:3	c.144+349G>A	intron	Intron 3 of 3	Prot: ENSP00000413316.1 UniProt:

HMOX1 ENST00000216117.9

TSL:1MANE Select

HGVSc / HGVSpc.144+349G>A

Exon rankIntron 2 of 4

intron

Prot: ENSP00000216117.8UniProt: P09601

HMOX1 ENST00000679074.1

HGVSc / HGVSpc.144+349G>A

Exon rankIntron 2 of 3

intron

Prot: ENSP00000503459.1UniProt: A0A7I2V3I1

HMOX1 ENST00000412893.5

TSL:3

HGVSc / HGVSpc.144+349G>A

Exon rankIntron 3 of 3

intron

Prot: ENSP00000413316.1UniProt: B1AHA8

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.153	AC:23311	Hom:3751	AN:152028	Cov:31
GnomAD4 genome	AF: 0.154	AC:23357	Hom:3755	AN:152146	Cov:31
TOPMed (Bravo)	AF: 0.170	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.118	AC:5869	Hom:839	AN:49538	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.133	AC:312	Hom:37	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0508	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0567	AC:17	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.0940	AC:331	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0480	AC:347	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.159	AC:28	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0471	AC:5777	Hom:133	AN:122692	Cov:
Turkish Variome	AF: 0.0776	AC:120	Hom:4	AN:1546	Cov:
UK10K	AF: 0.0558	AC:422	Hom:	AN:7562	Cov:

Showing 13 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	14
BayesDel_noAF	Benign	-0.86
CADD	Benign	13
DANN	Benign	0.78
GPN-Star LLR	N/A	0.27
GPN-Star score	N/A	-0.27
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.61
PromoterAI	N/A	-0.036	Neutral

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs8139532;

hg19: chr22-35779568;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar