chr6-46550407-G-A

Variant names:

• chr6-46550407-G-A
• NM_016593.5:c.1369C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016593.5(CYP39A1):​c.1369C>T​(p.Pro457Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP39A1 NM_016593.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP39A1	NM_016593.5	c.1369C>T	p.Pro457Ser	missense_variant	Exon 12 of 12	ENST00000275016.3	NP_057677.2
CYP39A1	NM_001278738.2	c.1309C>T	p.Pro437Ser	missense_variant	Exon 12 of 12		NP_001265667.1
CYP39A1	NM_001278739.2	c.853C>T	p.Pro285Ser	missense_variant	Exon 11 of 11		NP_001265668.1
CYP39A1	XM_017010924.2	c.1261C>T	p.Pro421Ser	missense_variant	Exon 11 of 11		XP_016866413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP39A1	ENST00000275016.3	c.1369C>T	p.Pro457Ser	missense_variant	Exon 12 of 12	1	NM_016593.5	ENSP00000275016.2
CYP39A1	ENST00000619708.4	c.853C>T	p.Pro285Ser	missense_variant	Exon 11 of 11	1		ENSP00000477769.1
RCAN2-DT	ENST00000657801.2	n.402+17892G>A		intron_variant	Intron 3 of 3
RCAN2-DT	ENST00000762069.1	n.378+17892G>A		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1369C>T (p.P457S) alteration is located in exon 12 (coding exon 12) of the CYP39A1 gene. This alteration results from a C to T substitution at nucleotide position 1369, causing the proline (P) at amino acid position 457 to be replaced by a serine (S). 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	Uncertain	0.53
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	.;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.7	.;M
PhyloP100		4.9
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.3	.;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.30
MutPred		0.49		.;Gain of sheet (P = 0.0827);
MVP		0.94
MPC		0.29
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.76
gMVP		0.75
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

hg19: chr6-46518144;