22-42628265-G-C

Variant names:

• chr22-42628265-G-C
• rs1800457
• NM_000398.7:c.350C>G

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.350C>G​(p.Thr117Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,613,922 control chromosomes in the GnomAD database, including 3,151 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T117A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.080 (1670 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (1481 hom.)
• Consequence: CYB5R3 NM_000398.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.08
• Publications: 23 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 (MetaRNN=0.0022090673).
• BP6: Variant 22-42628265-G-C is Benign according to our data. Variant chr22-42628265-G-C is described in ClinVar as Benign. ClinVar VariationId is 244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 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.350C>G	p.Thr117Ser	missense	Exon 5 of 9	NP_000389.1
	CYB5R3	NM_001171660.2		c.449C>G	p.Thr150Ser	missense	Exon 5 of 9	NP_001165131.1
	CYB5R3	NM_001129819.2		c.281C>G	p.Thr94Ser	missense	Exon 5 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.350C>G	p.Thr117Ser	missense	Exon 5 of 9	ENSP00000338461.6
	CYB5R3	ENST00000407332.6	TSL:1	c.368C>G	p.Thr123Ser	missense	Exon 5 of 9	ENSP00000384457.2
	CYB5R3	ENST00000470741.1	TSL:1	n.2484C>G		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes AF: 0.0802 AC: 12187 AN: 152042 Hom.: 1671 Cov.: 32

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.0498

GnomAD2 exomes AF: 0.0207 AC: 5217 AN: 251468 AF XY: 0.0151

Gnomad AFR exome AF: 0.286

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.00317

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000633

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.00815 AC: 11920 AN: 1461762 Hom.: 1481 Cov.: 32 AF XY: 0.00709 AC XY: 5156 AN XY: 727182

African (AFR) AF: 0.283 AC: 9488 AN: 33468

American (AMR) AF: 0.0141 AC: 631 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00333 AC: 87 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000684 AC: 59 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00988 AC: 57 AN: 5768

European-Non Finnish (NFE) AF: 0.000505 AC: 562 AN: 1111930

Other (OTH) AF: 0.0172 AC: 1036 AN: 60390

GnomAD4 genome AF: 0.0801 AC: 12190 AN: 152160 Hom.: 1670 Cov.: 32 AF XY: 0.0771 AC XY: 5738 AN XY: 74400

African (AFR) AF: 0.280 AC: 11608 AN: 41450

American (AMR) AF: 0.0263 AC: 402 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68024

Other (OTH) AF: 0.0492 AC: 104 AN: 2112

Alfa AF: 0.00431 Hom.: 12

Bravo AF: 0.0907

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.275 AC: 1211

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0258 AC: 3130

EpiCase AF: 0.000709

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21085059)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CYB5R3 POLYMORPHISM Benign:1

May 01, 2008

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.68	N
PhyloP100		3.1
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.15
Sift	Benign	0.10	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.070
MutPred		0.14		Gain of disorder (P = 0.0511)
MPC		0.036
ClinPred		0.016	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.28
Mutation Taster		=99/1	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: rs1800457; hg19: chr22-43024271; COSMIC: COSV61545441; COSMIC: COSV61545441;