Genetic Variant NM_016230.4:c.568A>G (chr6-83921085-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_016230.4(CYB5R4):c.568A>G(p.Ile190Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 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: 1.93

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]

CYB5R4 links:

RIPPLY2-CYB5R4 (HGNC:):

RIPPLY2-CYB5R4 links:

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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=0.12766173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5R4	NM_016230.4 link	c.568A>G	p.Ile190Val	missense_variant	Exon 8 of 16	ENST00000369681.10	NP_057314.2	Q7L1T6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5R4	ENST00000369681.10 link	c.568A>G	p.Ile190Val	missense_variant	Exon 8 of 16	1	NM_016230.4	ENSP00000358695.3		Q7L1T6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1343178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

666820

African (AFR)

AF:

0.00

AC:

AN:

28346

American (AMR)

AF:

0.00

AC:

AN:

27978

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22780

East Asian (EAS)

AF:

0.00

AC:

AN:

36062

South Asian (SAS)

AF:

0.00

AC:

AN:

74796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5206

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1042498

Other (OTH)

AF:

0.00

AC:

AN:

55192

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.568A>G (p.I190V) 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 568, causing the isoleucine (I) at amino acid position 190 to be replaced by a valine (V). 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

0.073

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.028

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.69

M_CAP

Benign

0.0036

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.3

PhyloP100

1.9

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.10

REVEL

Benign

0.032

Sift

Benign

0.26

Sift4G

Benign

0.50

Polyphen

0.0

Vest4

0.27

MutPred

0.56

Gain of catalytic residue at I190 (P = 0.0592);

MVP

0.35

MPC

0.12

ClinPred

0.29

GERP RS

2.3

Varity_R

0.040

gMVP

0.22

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over