chr16-4509433-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002134.4(HMOX2):ā€‹c.718G>Cā€‹(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 (ā˜…).

Frequency

Genomes: š‘“ 0.00059 ( 2 hom., cov: 32)
Exomes š‘“: 0.00070 ( 3 hom. )

Consequence

HMOX2
NM_002134.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.89
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.008799285).
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HMOX2NM_002134.4 linkuse as main transcriptc.718G>C p.Ala240Pro missense_variant 5/6 ENST00000570646.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HMOX2ENST00000570646.6 linkuse as main transcriptc.718G>C p.Ala240Pro missense_variant 5/61 NM_002134.4 P1P30519-1

Frequencies

GnomAD3 genomes
AF:
0.000611
AC:
93
AN:
152088
Hom.:
3
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 10, 2022The 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
LIST_S2
Benign
0.81
.;.;.;.;T;.;T;.;.;T
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

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

Other links and lift over

dbSNP: rs149714752; hg19: chr16-4559434; API