rs61743746

chr22-42619781-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000398.7(CYB5R3):c.898G>A(p.Val300Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,582,544 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (13 hom.)
• Consequence: CYB5R3 NM_000398.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.48

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a chain NADH-cytochrome b5 reductase 3 (size 299) in uniprot entity NB5R3_HUMAN there are 70 pathogenic changes around while only 8 benign (90%) in NM_000398.7
• BP4: Computational evidence support a benign effect (MetaRNN=0.00615865).
• BP6: Variant 22-42619781-C-T is Benign according to our data. Variant chr22-42619781-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 778955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00749 (1140/152248) while in subpopulation AFR AF= 0.0256 (1063/41546). AF 95% confidence interval is 0.0243. There are 15 homozygotes in gnomad4. There are 541 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB5R3	NM_000398.7	c.898G>A	p.Val300Ile	missense_variant	9/9	ENST00000352397.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB5R3	ENST00000352397.10	c.898G>A	p.Val300Ile	missense_variant	9/9	1	NM_000398.7	P3

Frequencies

GnomAD3 genomes AF: 0.00747 AC: 1136 AN: 152130 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0256

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: 0.000176

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00202 AC: 407 AN: 201626 Hom.: 5 AF XY: 0.00154 AC XY: 167 AN XY: 108648

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000382

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000165

Gnomad OTH exome AF: 0.000974

GnomAD4 exome AF: 0.000836 AC: 1196 AN: 1430296 Hom.: 13 Cov.: 32 AF XY: 0.000728 AC XY: 516 AN XY: 708648

Gnomad4 AFR exome AF: 0.0270

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.0000607

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000928

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00749 AC: 1140 AN: 152248 Hom.: 15 Cov.: 33 AF XY: 0.00727 AC XY: 541 AN XY: 74436

Gnomad4 AFR AF: 0.0256

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000960 Hom.: 1

Bravo AF: 0.00853

ESP6500AA AF: 0.0257 AC: 113

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00221 AC: 266

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 29, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	0.059
Dann	Benign	0.93
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.28	T;T;.;.;T
MetaRNN	Benign	0.0062	T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.67	N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.28	T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.0	.;B;.;.;.
Vest4		0.012
MVP		0.49
MPC		0.033
ClinPred		0.00091	T
GERP RS		-6.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.030
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs61743746; hg19: chr22-43015787;