chr6-46652515-C-G

Variant names:

• chr6-46652515-C-G
• rs12192544
• NM_016593.5:c.68G>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016593.5(CYP39A1):​c.68G>C​(p.Arg23Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,612,888 control chromosomes in the GnomAD database, including 38,328 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.17 (2676 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35652 hom.)
• Consequence: CYP39A1 NM_016593.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.154

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033367872).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP39A1	NM_016593.5	c.68G>C	p.Arg23Pro	missense_variant	Exon 1 of 12	ENST00000275016.3	NP_057677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP39A1	ENST00000275016.3	c.68G>C	p.Arg23Pro	missense_variant	Exon 1 of 12	1	NM_016593.5	ENSP00000275016.2
CYP39A1	ENST00000619708.4	c.-274G>C		5_prime_UTR_variant	Exon 1 of 11	1		ENSP00000477769.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25446 AN: 152022 Hom.: 2674 Cov.: 32

Gnomad AFR AF: 0.0498

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.180

GnomAD3 exomes AF: 0.201 AC: 50347 AN: 250374 Hom.: 5726 AF XY: 0.211 AC XY: 28545 AN XY: 135336

Gnomad AFR exome AF: 0.0451

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.133

Gnomad SAS exome AF: 0.284

Gnomad FIN exome AF: 0.223

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.216 AC: 316200 AN: 1460750 Hom.: 35652 Cov.: 33 AF XY: 0.220 AC XY: 159628 AN XY: 726620

Gnomad4 AFR exome AF: 0.0422

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.299

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.286

Gnomad4 FIN exome AF: 0.220

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.167 AC: 25447 AN: 152138 Hom.: 2676 Cov.: 32 AF XY: 0.168 AC XY: 12473 AN XY: 74382

Gnomad4 AFR AF: 0.0498

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.285

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.283

Gnomad4 FIN AF: 0.224

Gnomad4 NFE AF: 0.224

Gnomad4 OTH AF: 0.182

Alfa AF: 0.218 Hom.: 2989

Bravo AF: 0.151

TwinsUK AF: 0.221 AC: 818

ALSPAC AF: 0.229 AC: 881

ESP6500AA AF: 0.0520 AC: 229

ESP6500EA AF: 0.230 AC: 1980

ExAC AF: 0.202 AC: 24539

Asia WGS AF: 0.172 AC: 601 AN: 3478

EpiCase AF: 0.222

EpiControl AF: 0.223

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.18
Sift	Benign	0.12	T
Sift4G	Benign	0.21	T
Polyphen		0.96	D
Vest4		0.029
MPC		0.050
ClinPred		0.015	T
GERP RS		3.4
Varity_R		0.22
gMVP		0.55

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: rs12192544; hg19: chr6-46620252; COSMIC: COSV51494544; COSMIC: COSV51494544;