16-4476291-A-G

Variant names:

• chr16-4476291-A-G
• rs2270363
• ENST00000571291.5:n.-328T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000571291.5(NMRAL1):​n.-328T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 152,182 control chromosomes in the GnomAD database, including 41,962 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 0.74 (41944 hom., cov: 34)
  • Exomes 𝑓: 0.74 (18 hom.)
• Consequence: NMRAL1 ENST00000571291.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60
• Publications: 36 publications found

Genes affected

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]

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMOX2	NM_002134.4	c.-238A>G		upstream_gene_variant		ENST00000570646.6	NP_002125.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMOX2	ENST00000570646.6	c.-238A>G		upstream_gene_variant		1	NM_002134.4	ENSP00000459214.1

Frequencies

GnomAD3 genomes AF: 0.740 AC: 112535 AN: 152006 Hom.: 41891 Cov.: 34

Gnomad AFR AF: 0.784

Gnomad AMI AF: 0.472

Gnomad AMR AF: 0.714

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.759

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.743

Gnomad OTH AF: 0.737

GnomAD4 exome AF: 0.741 AC: 43 AN: 58 Hom.: 18 Cov.: 0 AF XY: 0.750 AC XY: 33 AN XY: 44

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.783 AC: 36 AN: 46

Other (OTH) AF: 1.00 AC: 4 AN: 4

GnomAD4 genome AF: 0.740 AC: 112641 AN: 152124 Hom.: 41944 Cov.: 34 AF XY: 0.735 AC XY: 54639 AN XY: 74350

African (AFR) AF: 0.784 AC: 32555 AN: 41522

American (AMR) AF: 0.715 AC: 10924 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 2484 AN: 3470

East Asian (EAS) AF: 0.642 AC: 3316 AN: 5166

South Asian (SAS) AF: 0.558 AC: 2687 AN: 4814

European-Finnish (FIN) AF: 0.759 AC: 8036 AN: 10586

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.743 AC: 50490 AN: 67974

Other (OTH) AF: 0.731 AC: 1543 AN: 2112

Alfa AF: 0.734 Hom.: 11506

Bravo AF: 0.741

Asia WGS AF: 0.547 AC: 1904 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.6
DANN	Benign	0.50
PhyloP100		-1.6
PromoterAI		-0.20	Neutral
Mutation Taster		=100/0	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: rs2270363; hg19: chr16-4526292;