Variant 22-42631386-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000398.7(CYB5R3):c.218T>C(p.Leu73Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,399,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

CYB5R3
NM_000398.7 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.04

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a domain FAD-binding FR-type (size 112) in uniprot entity NB5R3_HUMAN there are 37 pathogenic changes around while only 3 benign (93%) in NM_000398.7

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 22-42631386-A-G is Pathogenic according to our data. Variant chr22-42631386-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 246.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-42631386-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB5R3	NM_000398.7 linkuse as main transcript	c.218T>C	p.Leu73Pro	missense_variant	3/9	ENST00000352397.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB5R3	ENST00000352397.10 linkuse as main transcript	c.218T>C	p.Leu73Pro	missense_variant	3/9	1	NM_000398.7	P3	P00387-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000192

AC:

AN:

156222

Hom.:

AF XY:

0.0000122

AC XY:

AN XY:

82190

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000265

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000286

AC:

AN:

1399224

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000112

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Methemoglobinemia, type I

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

.;T;.;.;.;T

Eigen

Pathogenic

0.88

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;.;.;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

.;H;.;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.7

D;D;D;D;D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0030

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;.

Polyphen

1.0

.;D;.;.;.;.

Vest4

0.97

MutPred

0.95

.;Gain of disorder (P = 0.0331);.;.;.;.;

MVP

1.0

MPC

0.33

ClinPred

0.99

GERP RS

3.3

Varity_R

0.98

gMVP

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over