rs121965006

chr22-42628233-A-G

Variant summary

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

The NM_000398.7(CYB5R3):c.382T>C(p.Ser128Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,828 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. S128F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CYB5R3 NM_000398.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.85

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 helix (size 7) in uniprot entity NB5R3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr22-42628232-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 22-42628233-A-G is Pathogenic according to our data. Variant chr22-42628233-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 234.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-42628233-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB5R3	NM_000398.7	c.382T>C	p.Ser128Pro	missense_variant	5/9	ENST00000352397.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB5R3	ENST00000352397.10	c.382T>C	p.Ser128Pro	missense_variant	5/9	1	NM_000398.7	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251480 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461828 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

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	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;.;.;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0070	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;.
Polyphen		1.0	.;D;.;.;.;.
Vest4		0.97
MutPred		0.96		.;Loss of ubiquitination at K126 (P = 0.1223);.;.;.;.;
MVP		1.0
MPC		0.30
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
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: rs121965006; hg19: chr22-43024239;