6-83921083-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016230.4(CYB5R4):​c.566A>G​(p.Asp189Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000201 in 1,493,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

CYB5R4
NM_016230.4 missense, splice_region

Scores

1
18
Splicing: ADA: 0.0007713
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.45

Publications

0 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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11691922).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYB5R4NM_016230.4 linkc.566A>G p.Asp189Gly missense_variant, splice_region_variant Exon 8 of 16 ENST00000369681.10 NP_057314.2 Q7L1T6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYB5R4ENST00000369681.10 linkc.566A>G p.Asp189Gly missense_variant, splice_region_variant Exon 8 of 16 1 NM_016230.4 ENSP00000358695.3 Q7L1T6

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152188
Hom.:
0
Cov.:
32
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.00000522
AC:
1
AN:
191650
AF XY:
0.00000950
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000531
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:
0.00000149
AC:
2
AN:
1341718
Hom.:
0
Cov.:
27
AF XY:
0.00000150
AC XY:
1
AN XY:
666048
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
28350
American (AMR)
AF:
0.0000717
AC:
2
AN:
27906
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
22774
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36024
South Asian (SAS)
AF:
0.00
AC:
0
AN:
74600
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50250
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5198
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1041514
Other (OTH)
AF:
0.00
AC:
0
AN:
55102
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000657
AC:
1
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74350
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41454
American (AMR)
AF:
0.00
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68014
Other (OTH)
AF:
0.000478
AC:
1
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000825
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 13, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.566A>G (p.D189G) alteration is located in exon 8 (coding exon 8) of the CYB5R4 gene. This alteration results from a A to G substitution at nucleotide position 566, causing the aspartic acid (D) at amino acid position 189 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
18
DANN
Benign
0.92
DEOGEN2
Benign
0.021
T
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.069
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.64
T
M_CAP
Benign
0.0043
T
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.5
L
PhyloP100
1.5
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.43
N
REVEL
Benign
0.054
Sift
Benign
0.65
T
Sift4G
Benign
0.55
T
Polyphen
0.0
B
Vest4
0.32
MutPred
0.51
Loss of ubiquitination at K186 (P = 0.0618);
MVP
0.44
MPC
0.19
ClinPred
0.28
T
GERP RS
5.0
Varity_R
0.13
gMVP
0.61
Mutation Taster
=86/14
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00077
dbscSNV1_RF
Benign
0.012
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

Other links and lift over

dbSNP: rs750438129; hg19: chr6-84630802; API