Genetic Variant NM_016230.4:c.416A>C (chr6-83914419-A-C) – 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>C(p.Tyr139Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,379,816 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y139C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CYB5R4
NM_016230.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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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=0.060347825).

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>C	p.Tyr139Ser	missense	Exon 5 of 16	NP_057314.2	Q7L1T6
RIPPLY2-CYB5R4	NM_001400774.1		c.314A>C	p.Tyr105Ser	missense	Exon 6 of 17	NP_001387703.1	B2R7W7
RIPPLY2-CYB5R4	NR_174603.1		n.575A>C		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>C	p.Tyr139Ser	missense	Exon 5 of 16	ENSP00000358695.3	Q7L1T6
CYB5R4	ENST00000942770.1		c.416A>C	p.Tyr139Ser	missense	Exon 5 of 16	ENSP00000612829.1
CYB5R4	ENST00000942768.1		c.416A>C	p.Tyr139Ser	missense	Exon 5 of 16	ENSP00000612827.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000446

AC:

AN:

224232

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000610

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1379816

Hom.:

Cov.:

AF XY:

0.00

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:

0.0000529

AC:

AN:

37826

South Asian (SAS)

AF:

0.00

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:

0.00

AC:

AN:

1057962

Other (OTH)

AF:

0.00

AC:

AN:

56716

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

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.40

CADD

Benign

7.3

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.015

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.61

M_CAP

Benign

0.014

MetaRNN

Benign

0.060

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

PhyloP100

-0.13

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.28

REVEL

Benign

0.23

Sift

Benign

0.38

Sift4G

Benign

0.36

Polyphen

0.0010

Vest4

0.24

MutPred

0.54

Gain of relative solvent accessibility (P = 0.005)

MVP

0.72

MPC

0.20

ClinPred

0.025

GERP RS

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.088

gMVP

0.69

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over