rs137124

Positions:

• chr22-42619710-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000398.7(CYB5R3):​c.*63A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,475,154 control chromosomes in the GnomAD database, including 55,768 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (15806 hom., cov: 33)
  • Exomes 𝑓: 0.21 (39962 hom.)
• Consequence: CYB5R3 NM_000398.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.86

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-42619710-T-C is Benign according to our data. Variant chr22-42619710-T-C is described in ClinVar as [Benign]. Clinvar id is 1284044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB5R3	NM_000398.7	c.*63A>G		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.*63A>G		3_prime_UTR_variant	9/9	1	NM_000398.7	ENSP00000338461	P3

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55629 AN: 152030 Hom.: 15768 Cov.: 33

Gnomad AFR AF: 0.773

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.317

GnomAD4 exome AF: 0.212 AC: 280137 AN: 1323006 Hom.: 39962 Cov.: 26 AF XY: 0.211 AC XY: 136535 AN XY: 647254

Gnomad4 AFR exome AF: 0.795

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.160

Gnomad4 EAS exome AF: 0.654

Gnomad4 SAS exome AF: 0.251

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.177

Gnomad4 OTH exome AF: 0.258

GnomAD4 genome AF: 0.366 AC: 55726 AN: 152148 Hom.: 15806 Cov.: 33 AF XY: 0.363 AC XY: 26977 AN XY: 74380

Gnomad4 AFR AF: 0.774

Gnomad4 AMR AF: 0.229

Gnomad4 ASJ AF: 0.159

Gnomad4 EAS AF: 0.693

Gnomad4 SAS AF: 0.277

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.315

Alfa AF: 0.206 Hom.: 3625

Bravo AF: 0.389

Asia WGS AF: 0.446 AC: 1548 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.11
DANN	Benign	0.16
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: rs137124; hg19: chr22-43015716;