6-46596080-A-T

Position:

• chr6-46596080-A-T

Variant summary

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

The NM_016593.5(CYP39A1):​c.972T>A​(p.Asn324Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 1,607,776 control chromosomes in the GnomAD database, including 82,804 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.39 (13664 hom., cov: 31)
  • Exomes 𝑓: 0.29 (69140 hom.)
• Consequence: CYP39A1 NM_016593.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0120

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)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.743546E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP39A1	NM_016593.5	c.972T>A	p.Asn324Lys	missense_variant	8/12	ENST00000275016.3	NP_057677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP39A1	ENST00000275016.3	c.972T>A	p.Asn324Lys	missense_variant	8/12	1	NM_016593.5	ENSP00000275016	P1
CYP39A1	ENST00000619708.4	c.456T>A	p.Asn152Lys	missense_variant	7/11	1		ENSP00000477769
RCAN2-DT	ENST00000657801.1	n.287-9851A>T		intron_variant, non_coding_transcript_variant
CYP39A1	ENST00000480804.1	n.283T>A		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58578 AN: 151570 Hom.: 13616 Cov.: 31

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.381

GnomAD3 exomes AF: 0.347 AC: 86656 AN: 249442 Hom.: 17659 AF XY: 0.349 AC XY: 47066 AN XY: 134848

Gnomad AFR exome AF: 0.647

Gnomad AMR exome AF: 0.398

Gnomad ASJ exome AF: 0.367

Gnomad EAS exome AF: 0.317

Gnomad SAS exome AF: 0.579

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.339

GnomAD4 exome AF: 0.288 AC: 419965 AN: 1456088 Hom.: 69140 Cov.: 31 AF XY: 0.296 AC XY: 214116 AN XY: 724364

Gnomad4 AFR exome AF: 0.665

Gnomad4 AMR exome AF: 0.398

Gnomad4 ASJ exome AF: 0.362

Gnomad4 EAS exome AF: 0.400

Gnomad4 SAS exome AF: 0.571

Gnomad4 FIN exome AF: 0.228

Gnomad4 NFE exome AF: 0.245

Gnomad4 OTH exome AF: 0.326

GnomAD4 genome AF: 0.387 AC: 58680 AN: 151688 Hom.: 13664 Cov.: 31 AF XY: 0.388 AC XY: 28798 AN XY: 74148

Gnomad4 AFR AF: 0.640

Gnomad4 AMR AF: 0.398

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.346

Gnomad4 SAS AF: 0.587

Gnomad4 FIN AF: 0.220

Gnomad4 NFE AF: 0.250

Gnomad4 OTH AF: 0.384

Alfa AF: 0.280 Hom.: 4981

Bravo AF: 0.402

TwinsUK AF: 0.242 AC: 897

ALSPAC AF: 0.241 AC: 930

ESP6500AA AF: 0.628 AC: 2767

ESP6500EA AF: 0.267 AC: 2293

ExAC AF: 0.356 AC: 43177

Asia WGS AF: 0.512 AC: 1777 AN: 3474

EpiCase AF: 0.269

EpiControl AF: 0.270

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.5
DANN	Benign	0.72
DEOGEN2	Benign	0.0060	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.30	T;T
MetaRNN	Benign	0.000047	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	.;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.6	.;N
REVEL	Benign	0.22
Sift	Benign	1.0	.;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.079
MutPred		0.17		.;Gain of ubiquitination at N324 (P = 0.0337);
MPC		0.042
ClinPred		0.00054	T
GERP RS		-0.55
Varity_R		0.064
gMVP		0.25

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: rs7761731; hg19: chr6-46563817; COSMIC: COSV51497956;