6-83924488-T-G

Variant names:

• chr6-83924488-T-G
• rs1470114558
• NM_016230.4:c.710T>G

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.710T>G​(p.Val237Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V237A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CYB5R4 NM_016230.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51
• 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=0.20613101).

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.710T>G	p.Val237Gly	missense	Exon 10 of 16	NP_057314.2	Q7L1T6
	RIPPLY2-CYB5R4	NM_001400774.1		c.608T>G	p.Val203Gly	missense	Exon 11 of 17	NP_001387703.1	B2R7W7
	RIPPLY2-CYB5R4	NR_174603.1		n.869T>G		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.710T>G	p.Val237Gly	missense	Exon 10 of 16	ENSP00000358695.3	Q7L1T6
	CYB5R4	ENST00000942770.1		c.728T>G	p.Val243Gly	missense	Exon 10 of 16	ENSP00000612829.1
	CYB5R4	ENST00000942768.1		c.710T>G	p.Val237Gly	missense	Exon 10 of 16	ENSP00000612827.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461428 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727014

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111762

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.14
Sift	Benign	0.35	T
Sift4G	Benign	0.15	T
Polyphen		0.011	B
Vest4		0.47
MutPred		0.62		Loss of helix (P = 0.0041)
MVP		0.34
MPC		0.67
ClinPred		0.79	D
GERP RS		4.7
Varity_R		0.31
gMVP		0.68
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1470114558; hg19: chr6-84634207;