22-42631431-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000398.7(CYB5R3):c.173G>C(p.Arg58Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,399,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R58Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CYB5R3
NM_000398.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.82

Publications

13 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000398.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-42631431-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5R3	NM_000398.7 link	c.173G>C	p.Arg58Pro	missense_variant	Exon 3 of 9	ENST00000352397.10	NP_000389.1	P00387-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10 link	c.173G>C	p.Arg58Pro	missense_variant	Exon 3 of 9	1	NM_000398.7	ENSP00000338461.6		P00387-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000640

AC:

AN:

156360

AF XY:

0.0000122

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:

0.0000165

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000143

AC:

AN:

1399314

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

690180

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.00

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25178

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000185

AC:

AN:

1078946

Other (OTH)

AF:

0.00

AC:

AN:

58002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

.;D;.;.;.;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

D;D;.;.;D;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Pathogenic

4.5

.;H;.;.;.;.

PhyloP100

4.8

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.0

D;D;D;D;D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0020

D;D;D;D;D;D

Sift4G

Uncertain

0.027

D;D;D;D;D;.

Polyphen

1.0

.;D;.;.;.;.

Vest4

0.96

MutPred

0.79

.;Loss of MoRF binding (P = 0.0404);.;.;.;.;

MVP

0.97

MPC

0.32

ClinPred

0.99

GERP RS

1.2

Varity_R

0.99

gMVP

0.97

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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22-42631431-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over