Genetic Variant NM_016230.4:c.416A>G (chr6-83914419-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016230.4(CYB5R4):c.416A>G(p.Tyr139Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,379,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CYB5R4
NM_016230.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.128

Publications

1 publications found

Variant links:

Genes affected

CYB5R4 (HGNC:20147): (cytochrome b5 reductase 4) NCB5OR is a flavohemoprotein that contains functional domains found in both cytochrome b5 (CYB5A; MIM 613218) and CYB5 reductase (CYB5R3; MIM 613213) (Zhu et al., 1999 [PubMed 10611283]).[supplied by OMIM, Jan 2010]

CYB5R4 links:

RIPPLY2-CYB5R4 (HGNC:):

RIPPLY2-CYB5R4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.044132084).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016230.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYB5R4	NM_016230.4	MANE Select	c.416A>G	p.Tyr139Cys	missense	Exon 5 of 16	NP_057314.2	Q7L1T6
RIPPLY2-CYB5R4	NM_001400774.1		c.314A>G	p.Tyr105Cys	missense	Exon 6 of 17	NP_001387703.1	B2R7W7
RIPPLY2-CYB5R4	NR_174603.1		n.575A>G		non_coding_transcript_exon	Exon 6 of 18

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYB5R4	ENST00000369681.10	TSL:1 MANE Select	c.416A>G	p.Tyr139Cys	missense	Exon 5 of 16	ENSP00000358695.3	Q7L1T6
CYB5R4	ENST00000942770.1		c.416A>G	p.Tyr139Cys	missense	Exon 5 of 16	ENSP00000612829.1
CYB5R4	ENST00000942768.1		c.416A>G	p.Tyr139Cys	missense	Exon 5 of 16	ENSP00000612827.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000134

AC:

AN:

224232

AF XY:

0.0000246

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1379818

Hom.:

Cov.:

AF XY:

0.0000175

AC XY:

AN XY:

685074

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30734

American (AMR)

AF:

0.00

AC:

AN:

36444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24246

East Asian (EAS)

AF:

0.00

AC:

AN:

37826

South Asian (SAS)

AF:

0.000149

AC:

AN:

80516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5250

European-Non Finnish (NFE)

AF:

0.00000189

AC:

AN:

1057964

Other (OTH)

AF:

0.0000176

AC:

AN:

56716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.040

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.60

M_CAP

Benign

0.016

MetaRNN

Benign

0.044

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.0

PhyloP100

-0.13

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.14

REVEL

Benign

0.24

Sift

Benign

0.21

Sift4G

Benign

0.18

Polyphen

0.0

Vest4

0.18

MutPred

0.38

Loss of phosphorylation at Y139 (P = 0.0368)

MVP

0.75

MPC

0.18

ClinPred

0.036

GERP RS

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.073

gMVP

0.66

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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