rs121965016

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000398.7(CYB5R3):c.875G>A(p.Gly292Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000401 in 1,596,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

CYB5R3
NM_000398.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.91

Publications

8 publications found

Variant links:

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

CYB5R3 links:

ENSG00000289517 (HGNC:):

ENSG00000289517 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant 22-42619804-C-T is Pathogenic according to our data. Variant chr22-42619804-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5R3	NM_000398.7 link	c.875G>A	p.Gly292Asp	missense_variant	Exon 9 of 9	ENST00000352397.10	NP_000389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10 link	c.875G>A	p.Gly292Asp	missense_variant	Exon 9 of 9	1	NM_000398.7	ENSP00000338461.6
ENSG00000289517	ENST00000617178.5 link	n.410G>A		non_coding_transcript_exon_variant	Exon 4 of 14	1		ENSP00000482500.2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000320

AC:

AN:

218684

AF XY:

0.0000423

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000706

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000422

AC:

AN:

1443874

Hom.:

Cov.:

AF XY:

0.0000391

AC XY:

AN XY:

716700

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33360

American (AMR)

AF:

0.00

AC:

AN:

41650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25670

East Asian (EAS)

AF:

0.00

AC:

AN:

39052

South Asian (SAS)

AF:

0.00

AC:

AN:

83494

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000534

AC:

AN:

1105602

Other (OTH)

AF:

0.0000334

AC:

AN:

59872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000568638), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000544

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CYB5R3: PM3:Strong, PM2, PS3:Supporting -

Deficiency of cytochrome-b5 reductase

Pathogenic:1

Aug 01, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CYB5R3 c.875G>A (p.Gly292Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 218684 control chromosomes (gnomAD). c.875G>A has been reported in the literature in individuals affected with methemoglobinemia (Percy_2002, 2005, 2006). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant protein results in ~58% of normal enzymatic activity. The following publications have been ascertained in the context of this evaluation (PMID: 12393396, 15953014, 16469290). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

METHEMOGLOBINEMIA, TYPE I

Pathogenic:1

May 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

.;T;.;.;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.83

T;T;.;.;T

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.3

.;M;.;.;.

PhyloP100

4.9

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.2

D;D;D;D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.021

D;D;D;D;D

Sift4G

Uncertain

0.021

D;D;D;D;D

Polyphen

0.82

.;P;.;.;.

Vest4

0.61

MutPred

0.80

.;Gain of solvent accessibility (P = 0.0638);.;.;.;

MVP

0.99

MPC

0.30

ClinPred

0.98

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.82

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over