6-46636408-G-C

Variant names:

• chr6-46636408-G-C
• rs147866724
• NM_016593.5:c.713C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_016593.5(CYP39A1):​c.713C>G​(p.Ser238Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00402 in 1,605,750 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (14 hom.)
• Consequence: CYP39A1 NM_016593.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.18
• Publications: 9 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056509376).
• BP6: Variant 6-46636408-G-C is Benign according to our data. Variant chr6-46636408-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2656619.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP39A1	NM_016593.5	c.713C>G	p.Ser238Cys	missense_variant	Exon 5 of 12	ENST00000275016.3	NP_057677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP39A1	ENST00000275016.3	c.713C>G	p.Ser238Cys	missense_variant	Exon 5 of 12	1	NM_016593.5	ENSP00000275016.2
CYP39A1	ENST00000619708.4	c.197C>G	p.Ser66Cys	missense_variant	Exon 4 of 11	1		ENSP00000477769.1
CYP39A1	ENST00000480804.1	n.132C>G		non_coding_transcript_exon_variant	Exon 2 of 5	5

Frequencies

GnomAD3 genomes AF: 0.00319 AC: 485 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00506

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00311 AC: 769 AN: 247544 AF XY: 0.00302

Gnomad AFR exome AF: 0.000744

Gnomad AMR exome AF: 0.00195

Gnomad ASJ exome AF: 0.00370

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00526

Gnomad OTH exome AF: 0.00364

GnomAD4 exome AF: 0.00411 AC: 5970 AN: 1453486 Hom.: 14 Cov.: 29 AF XY: 0.00399 AC XY: 2881 AN XY: 722798

African (AFR) AF: 0.000842 AC: 28 AN: 33244

American (AMR) AF: 0.00197 AC: 87 AN: 44126

Ashkenazi Jewish (ASJ) AF: 0.00457 AC: 119 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39502

South Asian (SAS) AF: 0.0000355 AC: 3 AN: 84488

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53338

Middle Eastern (MID) AF: 0.00219 AC: 10 AN: 4560

European-Non Finnish (NFE) AF: 0.00485 AC: 5379 AN: 1108166

Other (OTH) AF: 0.00418 AC: 251 AN: 60034

GnomAD4 genome AF: 0.00319 AC: 485 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.00290 AC XY: 216 AN XY: 74440

African (AFR) AF: 0.000578 AC: 24 AN: 41558

American (AMR) AF: 0.00314 AC: 48 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00506 AC: 344 AN: 68020

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00434 Hom.: 1

Bravo AF: 0.00352

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00606 AC: 52

ExAC AF: 0.00308 AC: 374

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CYP39A1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0057	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.3	.;M
PhyloP100		4.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	.;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.014	.;D
Sift4G	Uncertain	0.054	T;T
Polyphen		0.99	.;D
Vest4		0.17
MVP		0.90
MPC		0.25
ClinPred		0.015	T
GERP RS		5.2
Varity_R		0.15
gMVP		0.30
Mutation Taster		=86/14	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: rs147866724; hg19: chr6-46604145;