Genetic Variant CYP39A1:p.Asn324Lys (chr6-46596080-A-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.972T>A(p.Asn324Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 1,607,776 control chromosomes in the GnomAD database, including 82,804 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.39 ( 13664 hom., cov: 31)

Exomes 𝑓: 0.29 ( 69140 hom. )

Consequence

CYP39A1
NM_016593.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0120

Publications

49 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:

RCAN2-DT (HGNC:55661): (RCAN2 divergent transcript)

RCAN2-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.743546E-5).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016593.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CYP39A1	NM_016593.5	MANE Select	c.972T>A	p.Asn324Lys	missense	Exon 8 of 12	NP_057677.2
CYP39A1	NM_001278738.2		c.912T>A	p.Asn304Lys	missense	Exon 8 of 12	NP_001265667.1
CYP39A1	NM_001278739.2		c.456T>A	p.Asn152Lys	missense	Exon 7 of 11	NP_001265668.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CYP39A1	ENST00000275016.3	TSL:1 MANE Select	c.972T>A	p.Asn324Lys	missense	Exon 8 of 12	ENSP00000275016.2
CYP39A1	ENST00000619708.4	TSL:1	c.456T>A	p.Asn152Lys	missense	Exon 7 of 11	ENSP00000477769.1
CYP39A1	ENST00000480804.1	TSL:5	n.283T>A		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes

AF:

0.386

AC:

58578

AN:

151570

Hom.:

13616

Cov.:

show subpopulations

Gnomad AFR

AF:

0.639

Gnomad AMI

AF:

0.142

Gnomad AMR

AF:

0.397

Gnomad ASJ

AF:

0.356

Gnomad EAS

AF:

0.348

Gnomad SAS

AF:

0.588

Gnomad FIN

AF:

0.220

Gnomad MID

AF:

0.475

Gnomad NFE

AF:

0.250

Gnomad OTH

AF:

0.381

GnomAD2 exomes

AF:

0.347

AC:

86656

AN:

249442

AF XY:

0.349

show subpopulations

Gnomad AFR exome

AF:

0.647

Gnomad AMR exome

AF:

0.398

Gnomad ASJ exome

AF:

0.367

Gnomad EAS exome

AF:

0.317

Gnomad FIN exome

AF:

0.222

Gnomad NFE exome

AF:

0.255

Gnomad OTH exome

AF:

0.339

GnomAD4 exome

AF:

0.288

AC:

419965

AN:

1456088

Hom.:

69140

Cov.:

AF XY:

0.296

AC XY:

214116

AN XY:

724364

show subpopulations

African (AFR)

AF:

0.665

AC:

22071

AN:

33184

American (AMR)

AF:

0.398

AC:

17614

AN:

44246

Ashkenazi Jewish (ASJ)

AF:

0.362

AC:

9421

AN:

26032

East Asian (EAS)

AF:

0.400

AC:

15805

AN:

39556

South Asian (SAS)

AF:

0.571

AC:

48771

AN:

85410

European-Finnish (FIN)

AF:

0.228

AC:

12150

AN:

53362

Middle Eastern (MID)

AF:

0.476

AC:

2731

AN:

5742

European-Non Finnish (NFE)

AF:

0.245

AC:

271820

AN:

1108412

Other (OTH)

AF:

0.326

AC:

19582

AN:

60144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

12617

25234

37852

50469

63086

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9630

19260

28890

38520

48150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.387

AC:

58680

AN:

151688

Hom.:

13664

Cov.:

AF XY:

0.388

AC XY:

28798

AN XY:

74148

show subpopulations

African (AFR)

AF:

0.640

AC:

26468

AN:

41372

American (AMR)

AF:

0.398

AC:

6049

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.356

AC:

1233

AN:

3468

East Asian (EAS)

AF:

0.346

AC:

1774

AN:

5124

South Asian (SAS)

AF:

0.587

AC:

2818

AN:

4802

European-Finnish (FIN)

AF:

0.220

AC:

2329

AN:

10564

Middle Eastern (MID)

AF:

0.459

AC:

135

AN:

294

European-Non Finnish (NFE)

AF:

0.250

AC:

16934

AN:

67832

Other (OTH)

AF:

0.384

AC:

811

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1596

3191

4787

6382

7978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

540

1080

1620

2160

2700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.280

Hom.:

4981

Bravo

AF:

0.402

TwinsUK

AF:

0.242

AC:

897

ALSPAC

AF:

0.241

AC:

930

ESP6500AA

AF:

0.628

AC:

2767

ESP6500EA

AF:

0.267

AC:

2293

ExAC

AF:

0.356

AC:

43177

Asia WGS

AF:

0.512

AC:

1777

AN:

3474

EpiCase

AF:

0.269

EpiControl

AF:

0.270

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.5

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.0060

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.30

MetaRNN

Benign

0.000047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.0

PhyloP100

-0.012

PrimateAI

Benign

0.36

PROVEAN

Benign

1.6

REVEL

Benign

0.22

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.079

MutPred

0.17

Gain of ubiquitination at N324 (P = 0.0337)

MPC

0.042

ClinPred

0.00054

GERP RS

-0.55

Varity_R

0.064

gMVP

0.25

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over