Genetic Variant CYB5R3:p.Cys204Ser (chr22-42627326-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_000398.7(CYB5R3):c.611G>C(p.Cys204Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. C204Y) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CYB5R3
NM_000398.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.84

Publications

0 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: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
hereditary methemoglobinemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYB5R3 links:

ENSG00000289517 (HGNC:):

ENSG00000289517 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-42627326-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 249.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYB5R3	NM_000398.7	MANE Select	c.611G>C	p.Cys204Ser	missense	Exon 7 of 9	NP_000389.1	P00387-1
CYB5R3	NM_001171660.2		c.710G>C	p.Cys237Ser	missense	Exon 7 of 9	NP_001165131.1	P00387-3
CYB5R3	NM_001129819.2		c.542G>C	p.Cys181Ser	missense	Exon 7 of 9	NP_001123291.1	P00387-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYB5R3	ENST00000352397.10	TSL:1 MANE Select	c.611G>C	p.Cys204Ser	missense	Exon 7 of 9	ENSP00000338461.6	P00387-1
CYB5R3	ENST00000407332.6	TSL:1	c.629G>C	p.Cys210Ser	missense	Exon 7 of 9	ENSP00000384457.2	A0A8J8Z3C6
CYB5R3	ENST00000470741.1	TSL:1	n.2745G>C		non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.3

PhyloP100

7.8

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.1

REVEL

Pathogenic

0.73

Sift

Uncertain

0.014

Sift4G

Benign

0.12

Polyphen

0.80

Vest4

0.84

MutPred

0.77

Gain of disorder (P = 0.0171)

MVP

0.99

MPC

0.26

ClinPred

0.99

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.95

gMVP

0.88

Mutation Taster

=16/84

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over