rs2071747

Variant names:

• chr22-35381192-G-C
• rs2071747
• NM_002133.3:c.19G>C

Your query was ambiguous. Multiple possible variants found:

• chr22-35381192-G-C
• chr22-35381192-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002133.3(HMOX1):​c.19G>C​(p.Asp7His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0509 in 1,547,162 control chromosomes in the GnomAD database, including 2,219 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D7E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.042 (161 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2058 hom.)
• Consequence: HMOX1 NM_002133.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.311
• Publications: 57 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: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002096802).
• BP6: Variant 22-35381192-G-C is Benign according to our data. Variant chr22-35381192-G-C is described in ClinVar as Benign. ClinVar VariationId is 1168542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

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.19G>C	p.Asp7His	missense	Exon 1 of 5	NP_002124.1	Q6FH11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMOX1	ENST00000216117.9	TSL:1 MANE Select	c.19G>C	p.Asp7His	missense	Exon 1 of 5	ENSP00000216117.8	P09601
	HMOX1	ENST00000679074.1		c.19G>C	p.Asp7His	missense	Exon 1 of 4	ENSP00000503459.1	A0A7I2V3I1
	HMOX1	ENST00000412893.5	TSL:3	c.19G>C	p.Asp7His	missense	Exon 2 of 4	ENSP00000413316.1	B1AHA8

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6317 AN: 152214 Hom.: 161 Cov.: 32

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0340

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0586

Gnomad SAS AF: 0.0221

Gnomad FIN AF: 0.0494

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0534

Gnomad OTH AF: 0.0420

GnomAD2 exomes AF: 0.0429 AC: 6202 AN: 144592 AF XY: 0.0419

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.0422

Gnomad ASJ exome AF: 0.0209

Gnomad EAS exome AF: 0.0529

Gnomad FIN exome AF: 0.0492

Gnomad NFE exome AF: 0.0543

Gnomad OTH exome AF: 0.0407

GnomAD4 exome AF: 0.0519 AC: 72432 AN: 1394830 Hom.: 2058 Cov.: 31 AF XY: 0.0513 AC XY: 35375 AN XY: 689346

African (AFR) AF: 0.0218 AC: 703 AN: 32226

American (AMR) AF: 0.0421 AC: 1540 AN: 36576

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 569 AN: 25236

East Asian (EAS) AF: 0.0721 AC: 2641 AN: 36614

South Asian (SAS) AF: 0.0245 AC: 1962 AN: 80004

European-Finnish (FIN) AF: 0.0470 AC: 1678 AN: 35696

Middle Eastern (MID) AF: 0.0139 AC: 79 AN: 5700

European-Non Finnish (NFE) AF: 0.0559 AC: 60575 AN: 1084516

Other (OTH) AF: 0.0461 AC: 2685 AN: 58262

GnomAD4 genome AF: 0.0415 AC: 6326 AN: 152332 Hom.: 161 Cov.: 32 AF XY: 0.0411 AC XY: 3059 AN XY: 74490

African (AFR) AF: 0.0243 AC: 1012 AN: 41578

American (AMR) AF: 0.0342 AC: 524 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3470

East Asian (EAS) AF: 0.0581 AC: 301 AN: 5178

South Asian (SAS) AF: 0.0224 AC: 108 AN: 4832

European-Finnish (FIN) AF: 0.0494 AC: 525 AN: 10624

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0534 AC: 3631 AN: 68024

Other (OTH) AF: 0.0411 AC: 87 AN: 2116

Alfa AF: 0.0336 Hom.: 26

Bravo AF: 0.0404

TwinsUK AF: 0.0539 AC: 200

ALSPAC AF: 0.0555 AC: 214

ESP6500AA AF: 0.0162 AC: 60

ESP6500EA AF: 0.0367 AC: 276

ExAC AF: 0.0314 AC: 3393

Asia WGS AF: 0.0370 AC: 128 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	N
PhyloP100		0.31
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.11
Sift	Uncertain	0.022	D
Sift4G	Benign	0.10	T
Polyphen		0.0010	B
Vest4		0.059
MPC		0.061
ClinPred		0.0028	T
GERP RS		2.4
PromoterAI		-0.047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.28
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2071747; hg19: chr22-35777185; COSMIC: COSV53340374; COSMIC: COSV53340374;