22-42619486-G-T

Variant names:

• chr22-42619486-G-T
• rs137123
• ENST00000470741.1:n.3327C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000470741.1(CYB5R3):​n.3327C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 481,864 control chromosomes in the GnomAD database, including 24,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (13022 hom., cov: 33)
  • Exomes 𝑓: 0.22 (11598 hom.)
• Consequence: CYB5R3 ENST00000470741.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.70
• Publications: 11 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

ENSG00000289517 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 22-42619486-G-T is Benign according to our data. Variant chr22-42619486-G-T is described in ClinVar as Benign. ClinVar VariationId is 1271243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000470741.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R3	NM_000398.7	MANE Select	c.*287C>A		3_prime_UTR	Exon 9 of 9	NP_000389.1
	CYB5R3	NM_001171660.2		c.*287C>A		3_prime_UTR	Exon 9 of 9	NP_001165131.1
	CYB5R3	NM_001129819.2		c.*287C>A		3_prime_UTR	Exon 9 of 9	NP_001123291.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R3	ENST00000470741.1	TSL:1	n.3327C>A		non_coding_transcript_exon	Exon 6 of 6
	CYB5R3	ENST00000352397.10	TSL:1 MANE Select	c.*287C>A		3_prime_UTR	Exon 9 of 9	ENSP00000338461.6
	CYB5R3	ENST00000407332.6	TSL:1	c.*287C>A		3_prime_UTR	Exon 9 of 9	ENSP00000384457.2

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51417 AN: 151850 Hom.: 13002 Cov.: 33

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.301

GnomAD4 exome AF: 0.221 AC: 72790 AN: 329896 Hom.: 11598 Cov.: 0 AF XY: 0.220 AC XY: 37997 AN XY: 172384

African (AFR) AF: 0.678 AC: 6347 AN: 9362

American (AMR) AF: 0.178 AC: 2621 AN: 14694

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 1444 AN: 10390

East Asian (EAS) AF: 0.640 AC: 13190 AN: 20612

South Asian (SAS) AF: 0.236 AC: 8892 AN: 37722

European-Finnish (FIN) AF: 0.171 AC: 3532 AN: 20698

Middle Eastern (MID) AF: 0.255 AC: 370 AN: 1452

European-Non Finnish (NFE) AF: 0.163 AC: 31929 AN: 196010

Other (OTH) AF: 0.236 AC: 4465 AN: 18956

GnomAD4 genome AF: 0.339 AC: 51491 AN: 151968 Hom.: 13022 Cov.: 33 AF XY: 0.336 AC XY: 24964 AN XY: 74302

African (AFR) AF: 0.688 AC: 28479 AN: 41384

American (AMR) AF: 0.219 AC: 3342 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 548 AN: 3470

East Asian (EAS) AF: 0.686 AC: 3528 AN: 5144

South Asian (SAS) AF: 0.273 AC: 1317 AN: 4818

European-Finnish (FIN) AF: 0.171 AC: 1814 AN: 10596

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11619 AN: 67964

Other (OTH) AF: 0.299 AC: 631 AN: 2110

Alfa AF: 0.262 Hom.: 1000

Bravo AF: 0.360

Asia WGS AF: 0.438 AC: 1519 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.043
DANN	Benign	0.59
PhyloP100		-1.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
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: rs137123; hg19: chr22-43015492; COSMIC: COSV52810176; COSMIC: COSV52810176;