Variant chr22-42619795-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000398.7(CYB5R3):c.884C>T(p.Thr295Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,440,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CYB5R3
NM_000398.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66

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:

CYB5R3 (HGNC:):

CYB5R3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain NADH-cytochrome b5 reductase 3 (size 299) in uniprot entity NB5R3_HUMAN there are 51 pathogenic changes around while only 3 benign (94%) in NM_000398.7

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15822092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB5R3	NM_000398.7 linkuse as main transcript	c.884C>T	p.Thr295Met	missense_variant	9/9	ENST00000352397.10	NP_000389.1	P00387-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5R3	ENST00000352397.10 linkuse as main transcript	c.884C>T	p.Thr295Met	missense_variant	9/9	1	NM_000398.7	ENSP00000338461.6		P00387-1
ENSG00000289517	ENST00000617178.5 linkuse as main transcript	n.419C>T		non_coding_transcript_exon_variant	4/14	1		ENSP00000482500.2		A0A087WZB1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000140

AC:

AN:

214696

Hom.:

AF XY:

0.00000862

AC XY:

AN XY:

115958

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000660

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000617

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:

0.00000278

AC:

AN:

1440486

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714614

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000731

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

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.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.082

.;T;.;.;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.59

T;T;.;.;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.16

T;T;T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.1

.;L;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.98

N;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.11

T;T;T;T;T

Sift4G

Benign

0.078

T;T;T;T;T

Polyphen

0.0010

.;B;.;.;.

Vest4

0.11

MutPred

0.23

.;Loss of phosphorylation at T295 (P = 0.0419);.;.;.;

MVP

0.93

MPC

0.054

ClinPred

0.18

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.41

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