chr6-46550418-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016593.5(CYP39A1):c.1358G>A(p.Gly453Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,412 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: 0.0000014 ( 0 hom. )

Consequence

CYP39A1
NM_016593.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.84

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP39A1	NM_016593.5 link	c.1358G>A	p.Gly453Asp	missense_variant	Exon 12 of 12	ENST00000275016.3	NP_057677.2	Q9NYL5
CYP39A1	NM_001278738.2 link	c.1298G>A	p.Gly433Asp	missense_variant	Exon 12 of 12		NP_001265667.1	Q9NYL5B7Z786
CYP39A1	NM_001278739.2 link	c.842G>A	p.Gly281Asp	missense_variant	Exon 11 of 11		NP_001265668.1	Q9NYL5A0A087WTD2
CYP39A1	XM_017010924.2 link	c.1250G>A	p.Gly417Asp	missense_variant	Exon 11 of 11		XP_016866413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP39A1	ENST00000275016.3 link	c.1358G>A	p.Gly453Asp	missense_variant	Exon 12 of 12	1	NM_016593.5	ENSP00000275016.2	Q9NYL5
CYP39A1	ENST00000619708.4 link	c.842G>A	p.Gly281Asp	missense_variant	Exon 11 of 11	1		ENSP00000477769.1	A0A087WTD2
RCAN2-DT	ENST00000657801.2 link	n.402+17903C>T		intron_variant	Intron 3 of 3
RCAN2-DT	ENST00000762069.1 link	n.378+17903C>T		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000805

AC:

AN:

248360

AF XY:

0.00000745

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000597

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:

0.00000137

AC:

AN:

1459412

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725930

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33386

American (AMR)

AF:

0.0000451

AC:

AN:

44348

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39570

South Asian (SAS)

AF:

0.00

AC:

AN:

85676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110918

Other (OTH)

AF:

0.00

AC:

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1358G>A (p.G453D) alteration is located in exon 12 (coding exon 12) of the CYP39A1 gene. This alteration results from a G to A substitution at nucleotide position 1358, causing the glycine (G) at amino acid position 453 to be replaced by an aspartic acid (D). 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

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.7

.;M

PhyloP100

3.8

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.7

.;D

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.77

MutPred

0.66

.;Gain of relative solvent accessibility (P = 0.09);

MVP

0.83

MPC

0.31

ClinPred

0.99

GERP RS

5.8

Varity_R

0.87

gMVP

0.74

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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chr6-46550418-C-T

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