rs149854354

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-63435185-C-A
• chr17-63435185-C-T

Variant summary

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

The NM_001915.4(CYB561):​c.464G>T​(p.Arg155Leu) 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 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 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. R155C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYB561 NM_001915.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• Publications: 0 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: 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=0.1455791).

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>T	p.Arg155Leu	missense	Exon 5 of 6	NP_001906.3
	CYB561	NM_001330421.2		c.485G>T	p.Arg162Leu	missense	Exon 5 of 6	NP_001317350.1	J3QRH5
	CYB561	NM_001017916.2		c.464G>T	p.Arg155Leu	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>T	p.Arg155Leu	missense	Exon 5 of 6	ENSP00000354028.3	P49447-1
	CYB561	ENST00000580691.5	TSL:1	c.623G>T	p.Arg208Leu	missense	Exon 5 of 6	ENSP00000462545.1	J3KSL5
	CYB561	ENST00000392975.6	TSL:1	c.464G>T	p.Arg155Leu	missense	Exon 5 of 6	ENSP00000376701.2	P49447-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461786 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Benign	0.95
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.15	T
PhyloP100		1.2
Sift4G	Pathogenic	0.0	D
Vest4		0.35
MVP		0.043
ClinPred		0.47	T
GERP RS		3.4
PromoterAI		-0.045	Neutral
Varity_R		0.13
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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;