16-4509433-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002134.4(HMOX2):c.718G>C(p.Ala240Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000691 in 1,614,064 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00059 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (3 hom.)
• Consequence: HMOX2 NM_002134.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008799285).
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMOX2	NM_002134.4	c.718G>C	p.Ala240Pro	missense_variant	5/6	ENST00000570646.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMOX2	ENST00000570646.6	c.718G>C	p.Ala240Pro	missense_variant	5/6	1	NM_002134.4	P1

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152088 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000883 AC: 222 AN: 251318 Hom.: 1 AF XY: 0.000906 AC XY: 123 AN XY: 135814

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000871

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.000702 AC: 1026 AN: 1461862 Hom.: 3 Cov.: 33 AF XY: 0.000755 AC XY: 549 AN XY: 727228

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00704

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000555

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152202 Hom.: 2 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74406

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00120 Hom.: 1

Bravo AF: 0.000767

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000725 AC: 88

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00130

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

The c.718G>C (p.A240P) alteration is located in exon 6 (coding exon 4) of the HMOX2 gene. This alteration results from a G to C substitution at nucleotide position 718, causing the alanine (A) at amino acid position 240 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T;T;T;T;T;.;T;T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.0088	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;M;M;M;M;.;M;M;.
MutationTaster	Benign	0.80	N;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N;.;N;.;.;N;.;N;N;.
REVEL	Benign	0.076
Sift	Benign	0.13	T;.;T;.;.;T;.;T;T;.
Sift4G	Benign	0.069	T;T;T;T;T;T;T;T;T;T
Polyphen		0.94	P;P;P;P;P;P;.;P;P;.
Vest4		0.55
MVP		0.38
MPC		0.20
ClinPred		0.014	T
GERP RS		4.4
Varity_R		0.45
gMVP		0.74

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

LitVar

Other links and lift over

dbSNP: rs149714752; hg19: chr16-4559434;