6-46588126-A-G

Variant names:

• chr6-46588126-A-G
• rs771986688
• NM_016593.5:c.1069T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016593.5(CYP39A1):​c.1069T>C​(p.Tyr357His) variant causes a missense change. The variant allele was found at a frequency of 0.0000412 in 1,575,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: CYP39A1 NM_016593.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.54

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37915403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP39A1	NM_016593.5	c.1069T>C	p.Tyr357His	missense_variant	Exon 9 of 12	ENST00000275016.3	NP_057677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP39A1	ENST00000275016.3	c.1069T>C	p.Tyr357His	missense_variant	Exon 9 of 12	1	NM_016593.5	ENSP00000275016.2
CYP39A1	ENST00000619708.4	c.553T>C	p.Tyr185His	missense_variant	Exon 8 of 11	1		ENSP00000477769.1
CYP39A1	ENST00000480804.1	n.380T>C		non_coding_transcript_exon_variant	Exon 5 of 5	5
RCAN2-DT	ENST00000657801.1	n.287-17805A>G		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000130 AC: 3 AN: 229994 Hom.: 0 AF XY: 0.0000161 AC XY: 2 AN XY: 124472

Gnomad AFR exome AF: 0.0000663

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000435 AC: 62 AN: 1423762 Hom.: 0 Cov.: 25 AF XY: 0.0000466 AC XY: 33 AN XY: 708114

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000532

Gnomad4 OTH exome AF: 0.0000510

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000529

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1069T>C (p.Y357H) alteration is located in exon 9 (coding exon 9) of the CYP39A1 gene. This alteration results from a T to C substitution at nucleotide position 1069, causing the tyrosine (Y) at amino acid position 357 to be replaced by a histidine (H). 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	Benign	0.17
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.084	.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	.;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.1	.;D
REVEL	Benign	0.20
Sift	Benign	0.19	.;T
Sift4G	Benign	0.23	T;T
Polyphen		0.28	.;B
Vest4		0.43
MutPred		0.67		.;Loss of stability (P = 0.1096);
MVP		0.71
MPC		0.064
ClinPred		0.15	T
GERP RS		3.6
Varity_R		0.12
gMVP		0.69

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: rs771986688; hg19: chr6-46555863;