NM_000398.7:c.22-18C>A

Variant names:

• chr22-42636864-G-T
• rs2285141
• NM_000398.7:c.22-18C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000398.7(CYB5R3):​c.22-18C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,611,294 control chromosomes in the GnomAD database, including 16,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1778 hom., cov: 32)
  • Exomes 𝑓: 0.12 (15111 hom.)
• Consequence: CYB5R3 NM_000398.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.336
• Publications: 20 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 22-42636864-G-T is Benign according to our data. Variant chr22-42636864-G-T is described in ClinVar as Benign. ClinVar VariationId is 256012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000398.7. 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.22-18C>A		intron	N/A	NP_000389.1
	CYB5R3	NM_001171660.2		c.121-18C>A		intron	N/A	NP_001165131.1
	CYB5R3	NM_001129819.2		c.-48-18C>A		intron	N/A	NP_001123291.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R3	ENST00000352397.10	TSL:1 MANE Select	c.22-18C>A		intron	N/A	ENSP00000338461.6
	CYB5R3	ENST00000407332.6	TSL:1	c.22-18C>A		intron	N/A	ENSP00000384457.2
	CYB5R3	ENST00000361740.9	TSL:2	c.22-18C>A		intron	N/A	ENSP00000354468.5

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18672 AN: 152102 Hom.: 1784 Cov.: 32

Gnomad AFR AF: 0.0900

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.0804

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.149 AC: 36798 AN: 246602 AF XY: 0.151

Gnomad AFR exome AF: 0.0908

Gnomad AMR exome AF: 0.0830

Gnomad ASJ exome AF: 0.0784

Gnomad EAS exome AF: 0.589

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.117 AC: 170561 AN: 1459074 Hom.: 15111 Cov.: 33 AF XY: 0.120 AC XY: 86846 AN XY: 725798

African (AFR) AF: 0.0925 AC: 3093 AN: 33448

American (AMR) AF: 0.0851 AC: 3791 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.0815 AC: 2129 AN: 26114

East Asian (EAS) AF: 0.564 AC: 22322 AN: 39544

South Asian (SAS) AF: 0.189 AC: 16299 AN: 86116

European-Finnish (FIN) AF: 0.156 AC: 8095 AN: 51982

Middle Eastern (MID) AF: 0.0951 AC: 548 AN: 5764

European-Non Finnish (NFE) AF: 0.0955 AC: 106172 AN: 1111228

Other (OTH) AF: 0.135 AC: 8112 AN: 60310

GnomAD4 genome AF: 0.123 AC: 18680 AN: 152220 Hom.: 1778 Cov.: 32 AF XY: 0.129 AC XY: 9601 AN XY: 74418

African (AFR) AF: 0.0902 AC: 3747 AN: 41564

American (AMR) AF: 0.104 AC: 1593 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 279 AN: 3468

East Asian (EAS) AF: 0.581 AC: 2995 AN: 5152

South Asian (SAS) AF: 0.229 AC: 1104 AN: 4824

European-Finnish (FIN) AF: 0.153 AC: 1620 AN: 10598

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6938 AN: 68006

Other (OTH) AF: 0.132 AC: 278 AN: 2110

Alfa AF: 0.109 Hom.: 1140

Bravo AF: 0.116

Asia WGS AF: 0.345 AC: 1197 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.085
DANN	Benign	0.69
PhyloP100		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=150/150

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: rs2285141; hg19: chr22-43032870; COSMIC: COSV61545179; COSMIC: COSV61545179;