rs75478217

Positions:

• chr22-42627680-C-G
• chr22-42627680-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000398.7(CYB5R3):​c.472G>C​(p.Ala158Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,932 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CYB5R3 NM_000398.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.86

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain NADH-cytochrome b5 reductase 3 (size 299) in uniprot entity NB5R3_HUMAN there are 51 pathogenic changes around while only 3 benign (94%) in NM_000398.7
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB5R3	NM_000398.7	c.472G>C	p.Ala158Pro	missense_variant	6/9	ENST00000352397.10	NP_000389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10	c.472G>C	p.Ala158Pro	missense_variant	6/9	1	NM_000398.7	ENSP00000338461.6
ENSG00000289517	ENST00000617178.5	n.7G>C		non_coding_transcript_exon_variant	1/14	1		ENSP00000482500.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460932 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726840

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;T;.;.;.;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;.;.;T;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.42	.;N;.;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D
REVEL	Pathogenic	0.66
Sift	Benign	0.16	T;T;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T;.
Polyphen		0.097	.;B;.;.;.;.
Vest4		0.65
MutPred		0.42		.;Gain of disorder (P = 0.0294);.;.;.;.;
MVP		0.96
MPC		0.28
ClinPred		0.98	D
GERP RS		3.7
Varity_R		0.82
gMVP		0.80

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: rs75478217; hg19: chr22-43023686;