22-42619773-T-C

Position:

• chr22-42619773-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_000398.7(CYB5R3):​c.906A>G​(p.Ter302Trpext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CYB5R3 NM_000398.7 stop_lost
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.04

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]

ENSG00000289517 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000398.7 Downstream stopcodon found after 8 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB5R3	NM_000398.7	c.906A>G	p.Ter302Trpext*?	stop_lost	9/9	ENST00000352397.10	NP_000389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10	c.906A>G	p.Ter302Trpext*?	stop_lost	9/9	1	NM_000398.7	ENSP00000338461.6
ENSG00000289517	ENST00000617178.5	n.441A>G		non_coding_transcript_exon_variant	4/14	1		ENSP00000482500.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424670 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 705376

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: 9.12e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary methemoglobinemia Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Traditional Chinese Medicine, Fujian Provincial Hospital

-

We found a 27 year old Chinese male patient with persistent cyanosis clinical phenotype, whose methemoglobin content accounts for 14.3% of all hemoglobin (normal reference value<1%), and the b5R enzyme activity of red blood cells is reduced. This is considered to be due to the presence of Methemoglobinemia, type I. Whole exome sequencing of the proband revealed two mutations in the CYB5R3 (NM:000398): c.611G>A (p.Cys204Tyr) and c.906A>G (p. * 302Trpext * 42). One of these mutations is inherited from the father, while the other is from the mother. CYB5R3 NM:000398.7: c.906A>G (NP:000398.1: p. * 302Trpext * 42), this mutation is consistent with Likely Pathogenic according to ACMG score and has not been reported so far. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.83
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Benign	0.54	D
Vest4		0.20
GERP RS		3.1

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-43015779;