22-42619789-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000398.7(CYB5R3):c.890G>A(p.Arg297His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,587,798 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (13 hom.)
• Consequence: CYB5R3 NM_000398.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.19

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 -11 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=0.007664025).
• BP6: Variant 22-42619789-C-T is Benign according to our data. Variant chr22-42619789-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 694657.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr22-42619789-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00158 (241/152262) while in subpopulation SAS AF= 0.00538 (26/4832). AF 95% confidence interval is 0.00377. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB5R3	NM_000398.7	c.890G>A	p.Arg297His	missense_variant	9/9	ENST00000352397.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB5R3	ENST00000352397.10	c.890G>A	p.Arg297His	missense_variant	9/9	1	NM_000398.7	P3

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 240 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00209 AC: 434 AN: 208038 Hom.: 2 AF XY: 0.00237 AC XY: 266 AN XY: 112172

Gnomad AFR exome AF: 0.000463

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.000657

Gnomad EAS exome AF: 0.0000631

Gnomad SAS exome AF: 0.00642

Gnomad FIN exome AF: 0.000135

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00230 AC: 3301 AN: 1435536 Hom.: 13 Cov.: 32 AF XY: 0.00247 AC XY: 1761 AN XY: 711722

Gnomad4 AFR exome AF: 0.000541

Gnomad4 AMR exome AF: 0.00144

Gnomad4 ASJ exome AF: 0.000666

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00680

Gnomad4 FIN exome AF: 0.0000628

Gnomad4 NFE exome AF: 0.00219

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00158 AC: 241 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.00167 AC XY: 124 AN XY: 74450

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00538

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00247

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00258 Hom.: 0

Bravo AF: 0.00150

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00169 AC: 204

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	CYB5R3: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

Neurodevelopmental delay Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Sep 22, 2018

- -

CYB5R3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 14, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.84	T;T;.;.;T
MetaRNN	Benign	0.0077	T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.9	N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.077	T;T;T;T;T
Sift4G	Benign	0.087	T;T;T;T;T
Polyphen		0.084	.;B;.;.;.
Vest4		0.11
MVP		0.96
MPC		0.043
ClinPred		0.029	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.60

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: rs76458556; hg19: chr22-43015795; COSMIC: COSV52809288; COSMIC: COSV52809288;