ENST00000470741.1:n.3103A>G

Variant names:

• chr22-42619710-T-C
• rs137124
• ENST00000470741.1:n.3103A>G

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.3103A>G 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 0.228 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 ENST00000470741.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.86
• Publications: 24 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=-0.9).
• BP6: Variant 22-42619710-T-C is Benign according to our data. Variant chr22-42619710-T-C is described in ClinVar as Benign. ClinVar VariationId 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.

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.*63A>G		3_prime_UTR	Exon 9 of 9	NP_000389.1
	CYB5R3	NM_001171660.2		c.*63A>G		3_prime_UTR	Exon 9 of 9	NP_001165131.1
	CYB5R3	NM_001129819.2		c.*63A>G		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.3103A>G		non_coding_transcript_exon	Exon 6 of 6
	ENSG00000289517	ENST00000617178.5	TSL:1	n.*63A>G		non_coding_transcript_exon	Exon 4 of 14	ENSP00000482500.2
	CYB5R3	ENST00000352397.10	TSL:1 MANE Select	c.*63A>G		3_prime_UTR	Exon 9 of 9	ENSP00000338461.6

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

African (AFR) AF: 0.795 AC: 24420 AN: 30706

American (AMR) AF: 0.176 AC: 5987 AN: 34000

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 3610 AN: 22540

East Asian (EAS) AF: 0.654 AC: 23037 AN: 35218

South Asian (SAS) AF: 0.251 AC: 18345 AN: 73222

European-Finnish (FIN) AF: 0.184 AC: 6264 AN: 34038

Middle Eastern (MID) AF: 0.265 AC: 1200 AN: 4526

European-Non Finnish (NFE) AF: 0.177 AC: 183005 AN: 1033432

Other (OTH) AF: 0.258 AC: 14269 AN: 55324

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

African (AFR) AF: 0.774 AC: 32108 AN: 41508

American (AMR) AF: 0.229 AC: 3502 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 550 AN: 3468

East Asian (EAS) AF: 0.693 AC: 3579 AN: 5162

South Asian (SAS) AF: 0.277 AC: 1338 AN: 4826

European-Finnish (FIN) AF: 0.176 AC: 1864 AN: 10604

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

European-Non Finnish (NFE) AF: 0.175 AC: 11906 AN: 67970

Other (OTH) AF: 0.315 AC: 664 AN: 2106

Alfa AF: 0.216 Hom.: 4865

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

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	-0.90
CADD	Benign	0.11
DANN	Benign	0.16
PhyloP100		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs137124; hg19: chr22-43015716; COSMIC: COSV107252598; COSMIC: COSV107252598;