NM_001915.4:c.464G>A

Variant names:

• chr17-63435185-C-T
• rs149854354
• NM_001915.4:c.464G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001915.4(CYB561):​c.464G>A​(p.Arg155His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000805 in 1,614,038 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 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. R155C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (3 hom.)
• Consequence: CYB561 NM_001915.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23
• Publications: 2 publications found

Genes affected

CYB561 (HGNC:2571): (cytochrome b561) Predicted to enable transmembrane monodehydroascorbate reductase activity. Predicted to be involved in ascorbate homeostasis. Predicted to be located in chromaffin granule membrane. Predicted to be active in lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

CYB561 Gene-Disease associations (from GenCC):

• orthostatic hypotension 2

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09137446).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001915.4. 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
	CYB561	NM_001915.4	MANE Select	c.464G>A	p.Arg155His	missense	Exon 5 of 6	NP_001906.3
	CYB561	NM_001330421.2		c.485G>A	p.Arg162His	missense	Exon 5 of 6	NP_001317350.1	J3QRH5
	CYB561	NM_001017916.2		c.464G>A	p.Arg155His	missense	Exon 5 of 6	NP_001017916.1	P49447-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB561	ENST00000360793.8	TSL:1 MANE Select	c.464G>A	p.Arg155His	missense	Exon 5 of 6	ENSP00000354028.3	P49447-1
	CYB561	ENST00000580691.5	TSL:1	c.623G>A	p.Arg208His	missense	Exon 5 of 6	ENSP00000462545.1	J3KSL5
	CYB561	ENST00000392975.6	TSL:1	c.464G>A	p.Arg155His	missense	Exon 5 of 6	ENSP00000376701.2	P49447-1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152258 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000414 AC: 104 AN: 251250 AF XY: 0.000420

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000775

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000852 AC: 1246 AN: 1461780 Hom.: 3 Cov.: 32 AF XY: 0.000842 AC XY: 612 AN XY: 727192

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00106 AC: 1183 AN: 1111984

Other (OTH) AF: 0.000447 AC: 27 AN: 60392

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74390

African (AFR) AF: 0.0000482 AC: 2 AN: 41474

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000708 Hom.: 1

Bravo AF: 0.000351

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000545

EpiControl AF: 0.000711

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	0.088
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Benign	0.96
Eigen	Benign	0.14
Eigen_PC	Benign	0.083
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.091	T
PhyloP100		1.2
Sift4G	Pathogenic	0.0	D
Vest4		0.37
MVP		0.043
ClinPred		0.072	T
GERP RS		3.4
PromoterAI		-0.011	Neutral
Varity_R		0.084
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs149854354; hg19: chr17-61512546; COSMIC: COSV62539494; COSMIC: COSV62539494;