6-46625485-G-C

Variant names:

• chr6-46625485-G-C
• rs149313145
• NM_016593.5:c.864C>G

Variant summary

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

The NM_016593.5(CYP39A1):​c.864C>G​(p.Tyr288*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y288Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CYP39A1 NM_016593.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.55
• Publications: 0 publications found

Genes affected

CYP39A1 (HGNC:17449): (cytochrome P450 family 39 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum protein is involved in the conversion of cholesterol to bile acids. Its substrates include the oxysterols 25-hydroxycholesterol, 27-hydroxycholesterol and 24-hydroxycholesterol. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP39A1	NM_016593.5	c.864C>G	p.Tyr288*	stop_gained	Exon 7 of 12	ENST00000275016.3	NP_057677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP39A1	ENST00000275016.3	c.864C>G	p.Tyr288*	stop_gained	Exon 7 of 12	1	NM_016593.5	ENSP00000275016.2
CYP39A1	ENST00000619708.4	c.348C>G	p.Tyr116*	stop_gained	Exon 6 of 11	1		ENSP00000477769.1
CYP39A1	ENST00000480804.1	n.175C>G		non_coding_transcript_exon_variant	Exon 3 of 5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457154 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724850

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.00 AC: 0 AN: 85212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109640

Other (OTH) AF: 0.0000166 AC: 1 AN: 60138

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	36
DANN	Uncertain	0.98
Eigen	Benign	-0.059
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.17	N
PhyloP100		1.5
Vest4		0.080
GERP RS		1.6
Mutation Taster		=40/160	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs149313145; hg19: chr6-46593222;