chr22-42627327-A-G

Position:

• chr22-42627327-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The ENST00000352397.10(CYB5R3):​c.610T>C​(p.Cys204Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,674 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 Pathogenic (no stars). 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYB5R3 ENST00000352397.10 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.25

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a mutagenesis_site No effect on NADH-cytochrome b5 reductase activity. (size 0) in uniprot entity NB5R3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000352397.10
• 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 id is 249.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 22-42627327-A-G is Pathogenic according to our data. Variant chr22-42627327-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 241.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-42627327-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB5R3	NM_000398.7	c.610T>C	p.Cys204Arg	missense_variant	7/9	ENST00000352397.10	NP_000389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10	c.610T>C	p.Cys204Arg	missense_variant	7/9	1	NM_000398.7	ENSP00000338461	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250898 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135746

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461674 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Methemoglobinemia type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;T;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;.;.;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.0	.;M;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.3	D;D;D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.012	D;D;D;D;D
Sift4G	Benign	0.073	T;T;T;T;T
Polyphen		0.99	.;D;.;.;.
Vest4		0.97
MutPred		0.90		.;Gain of disorder (P = 0.0332);.;.;.;
MVP		0.99
MPC		0.34
ClinPred		0.99	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs121965011; hg19: chr22-43023333;