Genetic Variant HMOX1:c.144+4T>C (chr22-35383230-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002133.3(HMOX1):c.144+4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0442 in 1,612,922 control chromosomes in the GnomAD database, including 1,739 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 116 hom., cov: 31)

Exomes 𝑓: 0.045 ( 1623 hom. )

Consequence

HMOX1
NM_002133.3 splice_region, intron

Scores

Splicing: ADA: 0.0002314

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.758

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 22-35383230-T-C is Benign according to our data. Variant chr22-35383230-T-C is described in ClinVar as [Benign]. Clinvar id is 1167966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.065 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMOX1	NM_002133.3 link	c.144+4T>C		splice_region_variant, intron_variant	Intron 2 of 4	ENST00000216117.9	NP_002124.1	P09601Q6FH11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMOX1	ENST00000216117.9 link	c.144+4T>C		splice_region_variant, intron_variant	Intron 2 of 4	1	NM_002133.3	ENSP00000216117.8		P09601

Frequencies

GnomAD3 genomes

AF:

0.0374

AC:

5687

AN:

152162

Hom.:

117

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0238

Gnomad AMI

AF:

0.104

Gnomad AMR

AF:

0.0452

Gnomad ASJ

AF:

0.0397

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0131

Gnomad FIN

AF:

0.0134

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0506

Gnomad OTH

AF:

0.0522

GnomAD3 exomes

AF:

0.0358

AC:

9000

AN:

251236

Hom.:

193

AF XY:

0.0363

AC XY:

4932

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.0243

Gnomad AMR exome

AF:

0.0336

Gnomad ASJ exome

AF:

0.0456

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0153

Gnomad FIN exome

AF:

0.0165

Gnomad NFE exome

AF:

0.0517

Gnomad OTH exome

AF:

0.0473

GnomAD4 exome

AF:

0.0449

AC:

65623

AN:

1460642

Hom.:

1623

Cov.:

AF XY:

0.0447

AC XY:

32462

AN XY:

726624

show subpopulations

Gnomad4 AFR exome

AF:

0.0248

Gnomad4 AMR exome

AF:

0.0351

Gnomad4 ASJ exome

AF:

0.0425

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0161

Gnomad4 FIN exome

AF:

0.0176

Gnomad4 NFE exome

AF:

0.0509

Gnomad4 OTH exome

AF:

0.0466

GnomAD4 genome

AF:

0.0373

AC:

5687

AN:

152280

Hom.:

116

Cov.:

AF XY:

0.0342

AC XY:

2546

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0238

Gnomad4 AMR

AF:

0.0451

Gnomad4 ASJ

AF:

0.0397

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0127

Gnomad4 FIN

AF:

0.0134

Gnomad4 NFE

AF:

0.0506

Gnomad4 OTH

AF:

0.0516

Alfa

AF:

0.0379

Hom.:

Bravo

AF:

0.0405

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.0586

EpiControl

AF:

0.0570

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.73

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00023

dbscSNV1_RF

Benign

0.028

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over