22-42619699-G-A

Position:

• chr22-42619699-G-A

Variant summary

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

The NM_000398.7(CYB5R3):​c.*74C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000757 in 1,441,418 control chromosomes in the GnomAD database, including 9 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 0.00058 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (7 hom.)
• Consequence: CYB5R3 NM_000398.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.592

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=-0.81).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000584 (89/152272) while in subpopulation SAS AF= 0.00746 (36/4826). AF 95% confidence interval is 0.00554. There are 2 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB5R3	NM_000398.7	c.*74C>T		3_prime_UTR_variant	9/9	ENST00000352397.10	NP_000389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10	c.*74C>T		3_prime_UTR_variant	9/9	1	NM_000398.7	ENSP00000338461	P3

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152154 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.000777 AC: 1002 AN: 1289146 Hom.: 7 Cov.: 23 AF XY: 0.000990 AC XY: 625 AN XY: 631054

Gnomad4 AFR exome AF: 0.0000667

Gnomad4 AMR exome AF: 0.000387

Gnomad4 ASJ exome AF: 0.0000457

Gnomad4 EAS exome AF: 0.0000285

Gnomad4 SAS exome AF: 0.00818

Gnomad4 FIN exome AF: 0.0000301

Gnomad4 NFE exome AF: 0.000350

Gnomad4 OTH exome AF: 0.000721

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152272 Hom.: 2 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74472

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.000366

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.2
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs76582006; hg19: chr22-43015705;