16-4475264-C-T

Position:

• chr16-4475264-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001127206.3(HMOX2):​c.-42+417C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 151,766 control chromosomes in the GnomAD database, including 38,153 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.71 (38153 hom., cov: 30)
• Consequence: HMOX2 NM_001127206.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0210

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]

NMRAL1 (HGNC:24987): (NmrA like redox sensor 1) This gene encodes an NADPH sensor protein that preferentially binds to NADPH. The encoded protein also negatively regulates the activity of NF-kappaB in a ubiquitylation-dependent manner. It plays a key role in cellular antiviral response by negatively regulating the interferon response factor 3-mediated expression of interferon beta. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMOX2	NM_001127206.3	c.-42+417C>T		intron_variant			NP_001120678.1
NMRAL1	NM_001351994.2	c.-273-472G>A		intron_variant			NP_001338923.1
NMRAL1	XM_047434381.1	c.-417-472G>A		intron_variant			XP_047290337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMOX2	ENST00000406590.6	c.-42+417C>T		intron_variant		5		ENSP00000385100.2
NMRAL1	ENST00000574733.5	c.-660-472G>A		intron_variant		5		ENSP00000458762.1
HMOX2	ENST00000575051.5	c.-42+417C>T		intron_variant		5		ENSP00000458797.1

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107335 AN: 151644 Hom.: 38106 Cov.: 30

Gnomad AFR AF: 0.708

Gnomad AMI AF: 0.461

Gnomad AMR AF: 0.697

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.749

Gnomad MID AF: 0.587

Gnomad NFE AF: 0.725

Gnomad OTH AF: 0.708

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.708 AC: 107433 AN: 151766 Hom.: 38153 Cov.: 30 AF XY: 0.704 AC XY: 52180 AN XY: 74144

Gnomad4 AFR AF: 0.708

Gnomad4 AMR AF: 0.697

Gnomad4 ASJ AF: 0.680

Gnomad4 EAS AF: 0.641

Gnomad4 SAS AF: 0.553

Gnomad4 FIN AF: 0.749

Gnomad4 NFE AF: 0.725

Gnomad4 OTH AF: 0.701

Alfa AF: 0.714 Hom.: 37733

Bravo AF: 0.707

Asia WGS AF: 0.538 AC: 1870 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.58

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: rs4786500; hg19: chr16-4525265;