NM_000398.7:c.510G>T

Variant names:

• chr22-42627642-C-A
• rs61743717
• NM_000398.7:c.510G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000398.7(CYB5R3):​c.510G>T​(p.Arg170Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R170G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CYB5R3 NM_000398.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.502
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a chain NADH-cytochrome b5 reductase 3 (size 299) in uniprot entity NB5R3_HUMAN there are 20 pathogenic changes around while only 7 benign (74%) in NM_000398.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-42627644-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2664646.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26021177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5R3	NM_000398.7	c.510G>T	p.Arg170Ser	missense_variant	Exon 6 of 9	ENST00000352397.10	NP_000389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10	c.510G>T	p.Arg170Ser	missense_variant	Exon 6 of 9	1	NM_000398.7	ENSP00000338461.6
ENSG00000289517	ENST00000617178.5	n.45G>T		non_coding_transcript_exon_variant	Exon 1 of 14	1		ENSP00000482500.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111994

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.32	.;T;.;.;.;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.47	T;T;.;.;T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.24	T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.3	.;L;.;.;.;.
PhyloP100		0.50
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D
REVEL	Benign	0.22
Sift	Benign	0.080	T;T;T;T;T;D
Sift4G	Benign	0.13	T;T;T;T;T;.
Polyphen		0.0020	.;B;.;.;.;.
Vest4		0.41
MutPred		0.41		.;Loss of MoRF binding (P = 0.0068);.;.;.;.;
MVP		0.87
MPC		0.043
ClinPred		0.68	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.48
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61743717; hg19: chr22-43023648;