ENST00000692152.1:c.-48-12741G>A

Variant names:

• chr22-42649587-C-T
• rs8190364
• ENST00000692152.1:c.-48-12741G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 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: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, 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=-0.83).
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000692152.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R3	NM_000398.7	MANE Select	c.-272G>A		upstream_gene	N/A	NP_000389.1	P00387-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R3	ENST00000692152.1		c.-48-12741G>A		intron	N/A	ENSP00000509317.1	P00387-2
	CYB5R3	ENST00000686129.1		c.-48-12741G>A		intron	N/A	ENSP00000508623.1	A0A8I5KVD2
	CYB5R3	ENST00000693716.1		n.250-12741G>A		intron	N/A

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

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 18

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00333 AC: 1 AN: 300

Other (OTH) AF: 0.00 AC: 0 AN: 20

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

African (AFR) AF: 0.00162 AC: 67 AN: 41412

American (AMR) AF: 0.00118 AC: 18 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.000204 AC: 1 AN: 4914

South Asian (SAS) AF: 0.000839 AC: 4 AN: 4770

European-Finnish (FIN) AF: 0.00856 AC: 90 AN: 10520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0109 AC: 740 AN: 67920

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.00979 Hom.: 1

Bravo AF: 0.00541

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.3
DANN	Benign	0.93
PhyloP100		-0.97
PromoterAI		-0.18	Neutral

Splicing

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

Other links and lift over

dbSNP: rs8190364; hg19: chr22-43045593;