chr22-42636736-C-T

Variant names:

• chr22-42636736-C-T
• rs5996200
• NM_000398.7:c.132G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000398.7(CYB5R3):​c.132G>A​(p.Pro44Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,612,544 control chromosomes in the GnomAD database, including 15,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1310 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14379 hom.)
• Consequence: CYB5R3 NM_000398.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.96
• Publications: 17 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 22-42636736-C-T is Benign according to our data. Variant chr22-42636736-C-T is described in ClinVar as Benign. ClinVar VariationId is 256011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000398.7. 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.132G>A	p.Pro44Pro	synonymous	Exon 2 of 9	NP_000389.1
	CYB5R3	NM_001171660.2		c.231G>A	p.Pro77Pro	synonymous	Exon 2 of 9	NP_001165131.1
	CYB5R3	NM_001129819.2		c.63G>A	p.Pro21Pro	synonymous	Exon 2 of 9	NP_001123291.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R3	ENST00000352397.10	TSL:1 MANE Select	c.132G>A	p.Pro44Pro	synonymous	Exon 2 of 9	ENSP00000338461.6
	CYB5R3	ENST00000407332.6	TSL:1	c.132G>A	p.Pro44Pro	synonymous	Exon 2 of 9	ENSP00000384457.2
	CYB5R3	ENST00000361740.9	TSL:2	c.132G>A	p.Pro44Pro	synonymous	Exon 2 of 10	ENSP00000354468.5

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18993 AN: 152146 Hom.: 1305 Cov.: 32

Gnomad AFR AF: 0.0986

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0366

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.113 AC: 28110 AN: 248000 AF XY: 0.113

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.0832

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.000820

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.135 AC: 197319 AN: 1460280 Hom.: 14379 Cov.: 33 AF XY: 0.133 AC XY: 96739 AN XY: 726368

African (AFR) AF: 0.0926 AC: 3100 AN: 33478

American (AMR) AF: 0.0886 AC: 3955 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4604 AN: 26118

East Asian (EAS) AF: 0.000454 AC: 18 AN: 39682

South Asian (SAS) AF: 0.0421 AC: 3624 AN: 86176

European-Finnish (FIN) AF: 0.138 AC: 7252 AN: 52416

Middle Eastern (MID) AF: 0.176 AC: 1013 AN: 5760

European-Non Finnish (NFE) AF: 0.149 AC: 165639 AN: 1111660

Other (OTH) AF: 0.134 AC: 8114 AN: 60346

GnomAD4 genome AF: 0.125 AC: 19018 AN: 152264 Hom.: 1310 Cov.: 32 AF XY: 0.122 AC XY: 9059 AN XY: 74446

African (AFR) AF: 0.0988 AC: 4105 AN: 41548

American (AMR) AF: 0.117 AC: 1796 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 593 AN: 3472

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5188

South Asian (SAS) AF: 0.0373 AC: 180 AN: 4828

European-Finnish (FIN) AF: 0.131 AC: 1384 AN: 10604

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10351 AN: 68008

Other (OTH) AF: 0.151 AC: 319 AN: 2114

Alfa AF: 0.145 Hom.: 2786

Bravo AF: 0.125

Asia WGS AF: 0.0370 AC: 134 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	2.7
DANN	Benign	0.92
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	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: rs5996200; hg19: chr22-43032742;