22-42649289-G-T

Variant names:

• chr22-42649289-G-T
• rs8190370
• NM_000398.7:c.21+6C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000398.7(CYB5R3):​c.21+6C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000117 in 855,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: CYB5R3 NM_000398.7 splice_region, intron
• Scores: Splicing: ADA: 0.00005001
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.24
• 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: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hereditary methemoglobinemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5R3	NM_000398.7	c.21+6C>A		splice_region_variant, intron_variant	Intron 1 of 8	ENST00000352397.10	NP_000389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10	c.21+6C>A		splice_region_variant, intron_variant	Intron 1 of 8	1	NM_000398.7	ENSP00000338461.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000117 AC: 1 AN: 855014 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 405288

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16126

American (AMR) AF: 0.00 AC: 0 AN: 2834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6226

East Asian (EAS) AF: 0.00 AC: 0 AN: 5584

South Asian (SAS) AF: 0.00 AC: 0 AN: 18610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1816

European-Non Finnish (NFE) AF: 0.00000130 AC: 1 AN: 770212

Other (OTH) AF: 0.00 AC: 0 AN: 29072

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.6
DANN	Benign	0.89
PhyloP100		-2.2
PromoterAI		0.097	Neutral
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		3.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.0080
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: rs8190370; hg19: chr22-43045295;