rs916321

Variant names:

• chr22-42645385-G-A
• rs916321
• NM_000398.7:c.21+3910C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-42645385-G-A
• chr22-42645385-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000398.7(CYB5R3):​c.21+3910C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 152,092 control chromosomes in the GnomAD database, including 8,565 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 0.32 (8565 hom., cov: 32)
• Consequence: CYB5R3 NM_000398.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.90
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• methemoglobinemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
• methemoglobinemia due to deficiency of methemoglobin reductase

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hereditary methemoglobinemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5R3	NM_000398.7	c.21+3910C>T		intron_variant	Intron 1 of 8	ENST00000352397.10	NP_000389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10	c.21+3910C>T		intron_variant	Intron 1 of 8	1	NM_000398.7	ENSP00000338461.6

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48694 AN: 151974 Hom.: 8550 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.311

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.320 AC: 48730 AN: 152092 Hom.: 8565 Cov.: 32 AF XY: 0.325 AC XY: 24139 AN XY: 74336

African (AFR) AF: 0.177 AC: 7360 AN: 41496

American (AMR) AF: 0.383 AC: 5847 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1185 AN: 3470

East Asian (EAS) AF: 0.290 AC: 1492 AN: 5148

South Asian (SAS) AF: 0.451 AC: 2170 AN: 4816

European-Finnish (FIN) AF: 0.397 AC: 4202 AN: 10590

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.371 AC: 25224 AN: 67986

Other (OTH) AF: 0.315 AC: 664 AN: 2110

Alfa AF: 0.352 Hom.: 5518

Bravo AF: 0.312

Asia WGS AF: 0.360 AC: 1249 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.16
DANN	Benign	0.88
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs916321; hg19: chr22-43041391;