6-46625485-G-A

Variant names:

• chr6-46625485-G-A
• rs149313145
• NM_016593.5:c.864C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_016593.5(CYP39A1):​c.864C>T​(p.Tyr288Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000574 in 1,609,276 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (1 hom.)
• Consequence: CYP39A1 NM_016593.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.55
• Publications: 4 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-46625485-G-A is Benign according to our data. Variant chr6-46625485-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3079613.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.55 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP39A1	NM_016593.5	c.864C>T	p.Tyr288Tyr	synonymous_variant	Exon 7 of 12	ENST00000275016.3	NP_057677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP39A1	ENST00000275016.3	c.864C>T	p.Tyr288Tyr	synonymous_variant	Exon 7 of 12	1	NM_016593.5	ENSP00000275016.2
CYP39A1	ENST00000619708.4	c.348C>T	p.Tyr116Tyr	synonymous_variant	Exon 6 of 11	1		ENSP00000477769.1
CYP39A1	ENST00000480804.1	n.175C>T		non_coding_transcript_exon_variant	Exon 3 of 5	5

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152022 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000842 AC: 210 AN: 249332 AF XY: 0.000928

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00115

Gnomad ASJ exome AF: 0.00668

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000504

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.000501 AC: 730 AN: 1457136 Hom.: 1 Cov.: 29 AF XY: 0.000523 AC XY: 379 AN XY: 724846

African (AFR) AF: 0.00216 AC: 72 AN: 33378

American (AMR) AF: 0.00117 AC: 52 AN: 44418

Ashkenazi Jewish (ASJ) AF: 0.00608 AC: 158 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.000364 AC: 31 AN: 85210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53180

Middle Eastern (MID) AF: 0.00315 AC: 18 AN: 5716

European-Non Finnish (NFE) AF: 0.000298 AC: 331 AN: 1109634

Other (OTH) AF: 0.00113 AC: 68 AN: 60136

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152140 Hom.: 6 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74366

African (AFR) AF: 0.00238 AC: 99 AN: 41552

American (AMR) AF: 0.00177 AC: 27 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67938

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.000949 Hom.: 0

Bravo AF: 0.00146

Asia WGS AF: 0.00202 AC: 7 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 17, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.2
DANN	Benign	0.25
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149313145; hg19: chr6-46593222; COSMIC: COSV51499182;