Genetic Variant CYBRD1:p.Ser15Leu (chr2-171522589-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_024843.4(CYBRD1):c.44C>T(p.Ser15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,611,586 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00095 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

CYBRD1
NM_024843.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.02

Publications

3 publications found

Variant links:

Genes affected

CYBRD1 (HGNC:20797): (cytochrome b reductase 1) This gene is a member of the cytochrome b(561) family that encodes an iron-regulated protein. It highly expressed in the duodenal brush border membrane. It has ferric reductase activity and is believed to play a physiological role in dietary iron absorption. [provided by RefSeq, Jul 2008]

CYBRD1 Gene-Disease associations (from GenCC):

hereditary hemochromatosis
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

CYBRD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009373933).

BP6

Variant 2-171522589-C-T is Benign according to our data. Variant chr2-171522589-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3039228.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024843.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYBRD1	NM_024843.4	MANE Select	c.44C>T	p.Ser15Leu	missense	Exon 1 of 4	NP_079119.3
CYBRD1	NM_001127383.2		c.44C>T	p.Ser15Leu	missense	Exon 1 of 3	NP_001120855.1	Q53TN4-2
CYBRD1	NM_001256909.2		c.19+298C>T		intron	N/A	NP_001243838.1	Q53TN4-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYBRD1	ENST00000321348.9	TSL:1 MANE Select	c.44C>T	p.Ser15Leu	missense	Exon 1 of 4	ENSP00000319141.4	Q53TN4-1
CYBRD1	ENST00000375252.3	TSL:1	c.44C>T	p.Ser15Leu	missense	Exon 1 of 3	ENSP00000364401.3	Q53TN4-2
CYBRD1	ENST00000858692.1		c.44C>T	p.Ser15Leu	missense	Exon 1 of 4	ENSP00000528751.1

Frequencies

GnomAD3 genomes

AF:

0.000953

AC:

145

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00181

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00119

AC:

291

AN:

243898

AF XY:

0.00124

show subpopulations

Gnomad AFR exome

AF:

0.000128

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.000821

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000425

Gnomad NFE exome

AF:

0.00240

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.00159

AC:

2318

AN:

1459300

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

1137

AN XY:

725616

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33468

American (AMR)

AF:

0.000203

AC:

AN:

44320

Ashkenazi Jewish (ASJ)

AF:

0.000656

AC:

AN:

25916

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.000176

AC:

AN:

85400

European-Finnish (FIN)

AF:

0.000807

AC:

AN:

53272

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00193

AC:

2140

AN:

1111224

Other (OTH)

AF:

0.00144

AC:

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

159

317

476

634

793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000952

AC:

145

AN:

152286

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41556

American (AMR)

AF:

0.000131

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00181

AC:

123

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00161

Hom.:

Bravo

AF:

0.00105

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00147

AC:

178

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

CYBRD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.080

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.81

M_CAP

Benign

0.047

MetaRNN

Benign

0.0094

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

2.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.80

REVEL

Benign

0.083

Sift

Benign

0.26

Sift4G

Benign

0.32

Polyphen

0.014

Vest4

0.16

MVP

0.51

MPC

0.37

ClinPred

0.058

GERP RS

4.0

PromoterAI

0.0047

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.28

gMVP

0.58

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over