6-46652398-C-T

Position:

• chr6-46652398-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016593.5(CYP39A1):​c.177+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0318 in 1,608,390 control chromosomes in the GnomAD database, including 3,549 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.068 (699 hom., cov: 32)
  • Exomes 𝑓: 0.028 (2850 hom.)
• Consequence: CYP39A1 NM_016593.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001010
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0550

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP39A1	NM_016593.5	c.177+8G>A		splice_region_variant, intron_variant		ENST00000275016.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP39A1	ENST00000275016.3	c.177+8G>A		splice_region_variant, intron_variant		1	NM_016593.5	P1
CYP39A1	ENST00000619708.4	c.-165+8G>A		splice_region_variant, intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0679 AC: 10331 AN: 152088 Hom.: 697 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.0664

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.00914

Gnomad OTH AF: 0.0592

GnomAD3 exomes AF: 0.0718 AC: 17595 AN: 245052 Hom.: 1728 AF XY: 0.0659 AC XY: 8753 AN XY: 132744

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.0334

Gnomad EAS exome AF: 0.0561

Gnomad SAS exome AF: 0.122

Gnomad FIN exome AF: 0.0206

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.0606

GnomAD4 exome AF: 0.0280 AC: 40790 AN: 1456184 Hom.: 2850 Cov.: 30 AF XY: 0.0296 AC XY: 21437 AN XY: 724290

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.245

Gnomad4 ASJ exome AF: 0.0321

Gnomad4 EAS exome AF: 0.0822

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.0194

Gnomad4 NFE exome AF: 0.00667

Gnomad4 OTH exome AF: 0.0400

GnomAD4 genome AF: 0.0681 AC: 10358 AN: 152206 Hom.: 699 Cov.: 32 AF XY: 0.0734 AC XY: 5462 AN XY: 74418

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.0346

Gnomad4 EAS AF: 0.0662

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.0241

Gnomad4 NFE AF: 0.00916

Gnomad4 OTH AF: 0.0605

Alfa AF: 0.0293 Hom.: 387

Bravo AF: 0.0807

Asia WGS AF: 0.128 AC: 446 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.0
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.0020
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

LitVar

Other links and lift over

dbSNP: rs9369628; hg19: chr6-46620135;