NM_016230.4:c.697G>C

Variant names:

• chr6-83924475-G-C
• rs1402506889
• NM_016230.4:c.697G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016230.4(CYB5R4):​c.697G>C​(p.Val233Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. V233F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYB5R4 NM_016230.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.535
• Publications: 0 publications found

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]

RIPPLY2-CYB5R4 (HGNC:):

ACMG classification

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=0.14897814).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R4	NM_016230.4	MANE Select	c.697G>C	p.Val233Leu	missense	Exon 10 of 16	NP_057314.2	Q7L1T6
	RIPPLY2-CYB5R4	NM_001400774.1		c.595G>C	p.Val199Leu	missense	Exon 11 of 17	NP_001387703.1	B2R7W7
	RIPPLY2-CYB5R4	NR_174603.1		n.856G>C		non_coding_transcript_exon	Exon 11 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R4	ENST00000369681.10	TSL:1 MANE Select	c.697G>C	p.Val233Leu	missense	Exon 10 of 16	ENSP00000358695.3	Q7L1T6
	CYB5R4	ENST00000942770.1		c.715G>C	p.Val239Leu	missense	Exon 10 of 16	ENSP00000612829.1
	CYB5R4	ENST00000942768.1		c.697G>C	p.Val233Leu	missense	Exon 10 of 16	ENSP00000612827.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461208 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726924

African (AFR) AF: 0.0000299 AC: 1 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111682

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.3
DANN	Benign	0.94
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.54
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.082
Sift	Benign	0.038	D
Sift4G	Benign	0.073	T
Polyphen		0.069	B
Vest4		0.24
MutPred		0.55		Gain of helix (P = 0.0325)
MVP		0.23
MPC		0.14
ClinPred		0.29	T
GERP RS		2.4
Varity_R		0.091
gMVP		0.46
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs1402506889; hg19: chr6-84634194;