6-46637926-A-T

Variant names:

• chr6-46637926-A-T
• rs755713016
• NM_016593.5:c.541T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016593.5(CYP39A1):​c.541T>A​(p.Ser181Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S181P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP39A1 NM_016593.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.82
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08415523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP39A1	NM_016593.5	c.541T>A	p.Ser181Thr	missense_variant	Exon 4 of 12	ENST00000275016.3	NP_057677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP39A1	ENST00000275016.3	c.541T>A	p.Ser181Thr	missense_variant	Exon 4 of 12	1	NM_016593.5	ENSP00000275016.2
CYP39A1	ENST00000619708.4	c.25T>A	p.Ser9Thr	missense_variant	Exon 3 of 11	1		ENSP00000477769.1
CYP39A1	ENST00000480804.1	n.-41T>A		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.19
DEOGEN2	Benign	0.012	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.36	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.084	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N
PhyloP100		2.8
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.030	.;N
REVEL	Benign	0.074
Sift	Benign	0.47	.;T
Sift4G	Benign	0.65	T;T
Polyphen		0.0040	.;B
Vest4		0.20
MutPred		0.53		.;Loss of disorder (P = 0.0781);
MVP		0.49
MPC		0.040
ClinPred		0.077	T
GERP RS		3.1
Varity_R		0.039
gMVP		0.21
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs755713016; hg19: chr6-46605663;