6-46625457-C-T

Position:

• chr6-46625457-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000275016.3(CYP39A1):​c.892G>A​(p.Ala298Thr) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP39A1 ENST00000275016.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.565

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04799819).
• BP6: Variant 6-46625457-C-T is Benign according to our data. Variant chr6-46625457-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3270628.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP39A1	NM_016593.5	c.892G>A	p.Ala298Thr	missense_variant	7/12	ENST00000275016.3	NP_057677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP39A1	ENST00000275016.3	c.892G>A	p.Ala298Thr	missense_variant	7/12	1	NM_016593.5	ENSP00000275016	P1
CYP39A1	ENST00000619708.4	c.376G>A	p.Ala126Thr	missense_variant	6/11	1		ENSP00000477769
CYP39A1	ENST00000480804.1	n.203G>A		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.7
DANN	Benign	0.078
DEOGEN2	Benign	0.023	.;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.90	.;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.050	.;N
REVEL	Benign	0.090
Sift	Benign	1.0	.;T
Sift4G	Benign	0.81	T;T
Polyphen		0.0010	.;B
Vest4		0.012
MutPred		0.49		.;Gain of methylation at K297 (P = 0.1);
MVP		0.54
MPC		0.038
ClinPred		0.039	T
GERP RS		-0.14
Varity_R		0.030
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs1775255770; hg19: chr6-46593194;