6-83914419-A-C

Variant names:

• chr6-83914419-A-C
• rs759241854
• NM_016230.4:c.416A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.128
• Publications: 1 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: 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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5R4	NM_016230.4	c.416A>C	p.Tyr139Ser	missense_variant	Exon 5 of 16	ENST00000369681.10	NP_057314.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5R4	ENST00000369681.10	c.416A>C	p.Tyr139Ser	missense_variant	Exon 5 of 16	1	NM_016230.4	ENSP00000358695.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000446 AC: 1 AN: 224232 AF XY: 0.00

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: 2 AN: 1379816 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 685074

African (AFR) AF: 0.00 AC: 0 AN: 30734

American (AMR) AF: 0.00 AC: 0 AN: 36444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24246

East Asian (EAS) AF: 0.0000529 AC: 2 AN: 37826

South Asian (SAS) AF: 0.00 AC: 0 AN: 80516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5250

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1057962

Other (OTH) AF: 0.00 AC: 0 AN: 56716

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	7.3
DANN	Benign	0.83
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.13
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.23
Sift	Benign	0.38	T
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.24
MutPred		0.54		Gain of relative solvent accessibility (P = 0.005);
MVP		0.72
MPC		0.20
ClinPred		0.025	T
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

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

Other links and lift over

dbSNP: rs759241854; hg19: chr6-84624138;