chr6-46587087-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_016593.5(CYP39A1):​c.1240T>C​(p.Cys414Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)

Consequence

CYP39A1
NM_016593.5 missense

Scores

13
3
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.43
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]
RCAN2-DT (HGNC:55661): (RCAN2 divergent transcript)

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a binding_site axial binding residue (size 0) in uniprot entity CP39A_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYP39A1NM_016593.5 linkuse as main transcriptc.1240T>C p.Cys414Arg missense_variant 10/12 ENST00000275016.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP39A1ENST00000275016.3 linkuse as main transcriptc.1240T>C p.Cys414Arg missense_variant 10/121 NM_016593.5 P1
RCAN2-DTENST00000657801.1 linkuse as main transcriptn.287-18844A>G intron_variant, non_coding_transcript_variant

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
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 26, 2024The c.1240T>C (p.C414R) alteration is located in exon 10 (coding exon 10) of the CYP39A1 gene. This alteration results from a T to C substitution at nucleotide position 1240, causing the cysteine (C) at amino acid position 414 to be replaced by an arginine (R). 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
0.95
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
.;T
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.83
T;T
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Uncertain
2.8
.;M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-12
.;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
.;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.98
MutPred
0.84
.;Loss of catalytic residue at C414 (P = 0.0325);
MVP
0.98
MPC
0.35
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.97
gMVP
0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-46554824; API