rs7284807

Variant names:

• chr22-42619381-C-G
• rs7284807
• NM_000398.7:c.*392G>C

Variant summary

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

The NM_001171660.2(CYB5R3):​c.*392G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 223,928 control chromosomes in the GnomAD database, including 409 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 0.039 (380 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (29 hom.)
• Consequence: CYB5R3 NM_001171660.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.76
• Publications: 7 publications found

Genes affected

CYB5R3 (HGNC:2873): (cytochrome b5 reductase 3) This gene encodes cytochrome b5 reductase, which includes a membrane-bound form in somatic cells (anchored in the endoplasmic reticulum, mitochondrial and other membranes) and a soluble form in erythrocytes. The membrane-bound form exists mainly on the cytoplasmic side of the endoplasmic reticulum and functions in desaturation and elongation of fatty acids, in cholesterol biosynthesis, and in drug metabolism. The erythrocyte form is located in a soluble fraction of circulating erythrocytes and is involved in methemoglobin reduction. The membrane-bound form has both membrane-binding and catalytic domains, while the soluble form has only the catalytic domain. Alternate splicing results in multiple transcript variants. Mutations in this gene cause methemoglobinemias. [provided by RefSeq, Jan 2010]

CYB5R3 Gene-Disease associations (from GenCC):

• methemoglobinemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
• methemoglobinemia due to deficiency of methemoglobin reductase

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hereditary methemoglobinemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289517 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171660.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R3	NM_000398.7	MANE Select	c.*392G>C		3_prime_UTR	Exon 9 of 9	NP_000389.1
	CYB5R3	NM_001171660.2		c.*392G>C		3_prime_UTR	Exon 9 of 9	NP_001165131.1
	CYB5R3	NM_001129819.2		c.*392G>C		3_prime_UTR	Exon 9 of 9	NP_001123291.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R3	ENST00000352397.10	TSL:1 MANE Select	c.*392G>C		3_prime_UTR	Exon 9 of 9	ENSP00000338461.6
	CYB5R3	ENST00000407332.6	TSL:1	c.*392G>C		3_prime_UTR	Exon 9 of 9	ENSP00000384457.2
	CYB5R3	ENST00000470741.1	TSL:1	n.3432G>C		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5916 AN: 152226 Hom.: 380 Cov.: 33

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0211

GnomAD4 exome AF: 0.00576 AC: 412 AN: 71584 Hom.: 29 Cov.: 0 AF XY: 0.00487 AC XY: 183 AN XY: 37540

African (AFR) AF: 0.120 AC: 349 AN: 2910

American (AMR) AF: 0.00560 AC: 24 AN: 4284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1872

East Asian (EAS) AF: 0.00 AC: 0 AN: 4380

South Asian (SAS) AF: 0.000591 AC: 5 AN: 8462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2816

Middle Eastern (MID) AF: 0.00813 AC: 2 AN: 246

European-Non Finnish (NFE) AF: 0.0000234 AC: 1 AN: 42756

Other (OTH) AF: 0.00804 AC: 31 AN: 3858

GnomAD4 genome AF: 0.0389 AC: 5928 AN: 152344 Hom.: 380 Cov.: 33 AF XY: 0.0372 AC XY: 2773 AN XY: 74498

African (AFR) AF: 0.136 AC: 5652 AN: 41570

American (AMR) AF: 0.0139 AC: 212 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68038

Other (OTH) AF: 0.0208 AC: 44 AN: 2112

Alfa AF: 0.0295 Hom.: 26

Bravo AF: 0.0446

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.0
DANN	Benign	0.55
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs7284807; hg19: chr22-43015387;