22-42649587-C-T

Position:

• chr22-42649587-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000692152.1(CYB5R3):​c.-48-12741G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00627 in 151,950 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0063 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (0 hom.)
• Consequence: CYB5R3 ENST00000692152.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.971

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00628 (952/151588) while in subpopulation NFE AF= 0.0109 (740/67920). AF 95% confidence interval is 0.0102. There are 5 homozygotes in gnomad4. There are 439 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000686129.1	c.-48-12741G>A		intron_variant				ENSP00000508623
CYB5R3	ENST00000692152.1	c.-48-12741G>A		intron_variant				ENSP00000509317
CYB5R3	ENST00000693716.1	n.250-12741G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00628 AC: 952 AN: 151472 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.000838

Gnomad FIN AF: 0.00856

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00575

GnomAD4 exome AF: 0.00276 AC: 1 AN: 362 Hom.: 0 Cov.: 0 AF XY: 0.00459 AC XY: 1 AN XY: 218

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: 0.00333

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00628 AC: 952 AN: 151588 Hom.: 5 Cov.: 32 AF XY: 0.00593 AC XY: 439 AN XY: 74026

Gnomad4 AFR AF: 0.00162

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000204

Gnomad4 SAS AF: 0.000839

Gnomad4 FIN AF: 0.00856

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00979 Hom.: 1

Bravo AF: 0.00541

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.3
DANN	Benign	0.93

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs8190364; hg19: chr22-43045593;