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

Variant summary

Our verdict is Benign. The variant received -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

Publications

6 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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

GnomAD2 exomes

AF:

0.0718

AC:

17595

AN:

245052

AF XY:

0.0659

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 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

African (AFR)

AF:

0.139

AC:

4621

AN:

33202

American (AMR)

AF:

0.245

AC:

10710

AN:

43690

Ashkenazi Jewish (ASJ)

AF:

0.0321

AC:

825

AN:

25670

East Asian (EAS)

AF:

0.0822

AC:

3255

AN:

39588

South Asian (SAS)

AF:

0.119

AC:

10134

AN:

85174

European-Finnish (FIN)

AF:

0.0194

AC:

1034

AN:

53224

Middle Eastern (MID)

AF:

0.0708

AC:

405

AN:

5722

European-Non Finnish (NFE)

AF:

0.00667

AC:

7399

AN:

1109768

Other (OTH)

AF:

0.0400

AC:

2407

AN:

60146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1587

3174

4762

6349

7936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0681

AC:

10358

AN:

152206

Hom.:

699

Cov.:

AF XY:

0.0734

AC XY:

5462

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.133

AC:

5519

AN:

41508

American (AMR)

AF:

0.177

AC:

2708

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0346

AC:

120

AN:

3470

East Asian (EAS)

AF:

0.0662

AC:

343

AN:

5184

South Asian (SAS)

AF:

0.133

AC:

639

AN:

4820

European-Finnish (FIN)

AF:

0.0241

AC:

256

AN:

10606

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00916

AC:

623

AN:

68014

Other (OTH)

AF:

0.0605

AC:

128

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

466

931

1397

1862

2328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0339

Hom.:

577

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

(source)

DANN

Benign

0.78

PhyloP100

-0.055

PromoterAI

0.063

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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6-46652398-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over