17-63437504-T-A

Position:

• chr17-63437504-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001915.4(CYB561):​c.44A>T​(p.Tyr15Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYB561 NM_001915.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.524

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18083915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB561	NM_001915.4	c.44A>T	p.Tyr15Phe	missense_variant	2/6	ENST00000360793.8	NP_001906.3
CYB561	NM_001330421.2	c.65A>T	p.Tyr22Phe	missense_variant	2/6		NP_001317350.1
CYB561	NM_001017916.2	c.44A>T	p.Tyr15Phe	missense_variant	2/6		NP_001017916.1
CYB561	NM_001017917.2	c.44A>T	p.Tyr15Phe	missense_variant	2/6		NP_001017917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB561	ENST00000360793.8	c.44A>T	p.Tyr15Phe	missense_variant	2/6	1	NM_001915.4	ENSP00000354028.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

The c.44A>T (p.Y15F) alteration is located in exon 2 (coding exon 1) of the CYB561 gene. This alteration results from a A to T substitution at nucleotide position 44, causing the tyrosine (Y) at amino acid position 15 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.066	T;T;.;T;.;T;.;T;.;T;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.88	.;.;D;D;D;.;D;D;D;.;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.7	L;L;.;L;.;L;L;.;.;L;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.13	N;N;.;N;.;.;N;N;.;.;.;.
REVEL	Benign	0.12
Sift	Benign	0.22	T;T;.;T;.;.;T;T;.;.;.;.
Sift4G	Benign	0.36	T;T;T;T;T;T;T;T;T;.;.;.
Polyphen		0.93	P;P;.;P;.;P;.;D;.;P;.;.
Vest4		0.32
MutPred		0.37		.;.;.;.;.;.;.;Loss of helix (P = 0.0196);.;.;.;.;
MVP		0.30
MPC		0.33
ClinPred		0.45	T
GERP RS		3.1
La Branchor		0.89
Varity_R		0.092
gMVP		0.14

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-61514865;