Genetic Variant CYP39A1:p.Pro382Ala (chr6-46588051-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_016593.5(CYP39A1):c.1144C>G(p.Pro382Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,425,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CYP39A1
NM_016593.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.85

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP39A1	NM_016593.5 link	c.1144C>G	p.Pro382Ala	missense_variant	Exon 9 of 12	ENST00000275016.3	NP_057677.2	Q9NYL5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP39A1	ENST00000275016.3 link	c.1144C>G	p.Pro382Ala	missense_variant	Exon 9 of 12	1	NM_016593.5	ENSP00000275016.2		Q9NYL5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000426

AC:

AN:

234984

AF XY:

0.00000785

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1425778

Hom.:

Cov.:

AF XY:

0.00000423

AC XY:

AN XY:

709514

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32052

American (AMR)

AF:

0.00

AC:

AN:

41342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25554

East Asian (EAS)

AF:

0.00

AC:

AN:

37836

South Asian (SAS)

AF:

0.0000370

AC:

AN:

81180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090398

Other (OTH)

AF:

0.00

AC:

AN:

58928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1144C>G (p.P382A) alteration is located in exon 9 (coding exon 9) of the CYP39A1 gene. This alteration results from a C to G substitution at nucleotide position 1144, causing the proline (P) at amino acid position 382 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.096

.;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.049

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.32

MutationAssessor

Uncertain

2.8

.;M

PhyloP100

7.8

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-7.6

.;D

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.80

MutPred

0.90

.;Loss of disorder (P = 0.0466);

MVP

0.93

MPC

0.23

ClinPred

1.0

GERP RS

6.1

Varity_R

0.74

gMVP

0.64

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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6-46588051-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over