Genetic Variant CYP39A1:c.177+8G>A (chr6-46652398-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Variant links:

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]

CYP39A1 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
CYP39A1	NM_016593.5 link	c.177+8G>A		splice_region_variant, intron_variant	Intron 1 of 11	ENST00000275016.3	NP_057677.2	Q9NYL5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP39A1	ENST00000275016.3 link	c.177+8G>A		splice_region_variant, intron_variant	Intron 1 of 11	1	NM_016593.5	ENSP00000275016.2		Q9NYL5
CYP39A1	ENST00000619708.4 link	c.-165+8G>A		splice_region_variant, intron_variant	Intron 1 of 10	1		ENSP00000477769.1		A0A087WTD2

Frequencies

GnomAD3 genomes

AF:

0.0679

AC:

10331

AN:

152088

Hom.:

697

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0296

AC XY:

21437

AN XY:

724290

show subpopulations

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.:

AF XY:

0.0734

AC XY:

5462

AN XY:

74418

show subpopulations

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over