NM_000398.7:c.*278G>T

Variant names:

• chr22-42619495-C-A
• rs145166392
• NM_000398.7:c.*278G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000398.7(CYB5R3):​c.*278G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00304 in 509,546 control chromosomes in the GnomAD database, including 18 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 0.0075 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: CYB5R3 NM_000398.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.26
• 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

ENSG00000289517 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00751 (1142/152144) while in subpopulation AFR AF = 0.0257 (1066/41508). AF 95% confidence interval is 0.0244. There are 15 homozygotes in GnomAd4. There are 541 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

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.*278G>T		3_prime_UTR	Exon 9 of 9	NP_000389.1	P00387-1
	CYB5R3	NM_001171660.2		c.*278G>T		3_prime_UTR	Exon 9 of 9	NP_001165131.1	P00387-3
	CYB5R3	NM_001129819.2		c.*278G>T		3_prime_UTR	Exon 9 of 9	NP_001123291.1	P00387-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R3	ENST00000352397.10	TSL:1 MANE Select	c.*278G>T		3_prime_UTR	Exon 9 of 9	ENSP00000338461.6	P00387-1
	CYB5R3	ENST00000407332.6	TSL:1	c.*278G>T		3_prime_UTR	Exon 9 of 9	ENSP00000384457.2	A0A8J8Z3C6
	CYB5R3	ENST00000470741.1	TSL:1	n.3318G>T		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.00749 AC: 1138 AN: 152026 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00432

GnomAD4 exome AF: 0.00114 AC: 406 AN: 357402 Hom.: 3 Cov.: 0 AF XY: 0.000990 AC XY: 185 AN XY: 186818

African (AFR) AF: 0.0267 AC: 280 AN: 10480

American (AMR) AF: 0.00213 AC: 33 AN: 15518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11228

East Asian (EAS) AF: 0.00 AC: 0 AN: 24214

South Asian (SAS) AF: 0.0000501 AC: 2 AN: 39946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22488

Middle Eastern (MID) AF: 0.00189 AC: 3 AN: 1584

European-Non Finnish (NFE) AF: 0.000175 AC: 37 AN: 211320

Other (OTH) AF: 0.00247 AC: 51 AN: 20624

GnomAD4 genome AF: 0.00751 AC: 1142 AN: 152144 Hom.: 15 Cov.: 33 AF XY: 0.00727 AC XY: 541 AN XY: 74380

African (AFR) AF: 0.0257 AC: 1066 AN: 41508

American (AMR) AF: 0.00321 AC: 49 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67996

Other (OTH) AF: 0.00427 AC: 9 AN: 2106

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00852

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.13
DANN	Benign	0.84
PhyloP100		-5.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism

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: rs145166392; hg19: chr22-43015501;