2-218782183-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_000784.4(CYP27A1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000026 in 1,536,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

CYP27A1
NM_000784.4 start_lost

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.289

Publications

9 publications found

Variant links:

Genes affected

CYP27A1 (HGNC:2605): (cytochrome P450 family 27 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 mitochondrial protein oxidizes cholesterol intermediates as part of the bile synthesis pathway. Since the conversion of cholesterol to bile acids is the major route for removing cholesterol from the body, this protein is important for overall cholesterol homeostasis. Mutations in this gene cause cerebrotendinous xanthomatosis, a rare autosomal recessive lipid storage disease. [provided by RefSeq, Jul 2008]

CYP27A1 Gene-Disease associations (from GenCC):

cerebrotendinous xanthomatosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Genomics England PanelApp, G2P

CYP27A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 29 pathogenic variants. Next in-frame start position is after 95 codons. Genomic position: 218809604. Lost 0.177 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 9	ENST00000258415.9	NP_000775.1	Q02318

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP27A1	ENST00000258415.9 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 9	1	NM_000784.4	ENSP00000258415.4	Q02318
CYP27A1	ENST00000445971.1 link	n.1A>G		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000404945.1	F8WD90
CYP27A1	ENST00000466602.1 link	n.10A>G		non_coding_transcript_exon_variant	Exon 1 of 3	2
CYP27A1	ENST00000494263.5 link	n.435A>G		non_coding_transcript_exon_variant	Exon 1 of 7	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000751

AC:

AN:

133202

AF XY:

0.0000138

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000217

AC:

AN:

1384076

Hom.:

Cov.:

AF XY:

0.00000293

AC XY:

AN XY:

683098

show subpopulations

African (AFR)

AF:

0.0000319

AC:

AN:

31346

American (AMR)

AF:

0.00

AC:

AN:

35632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25110

East Asian (EAS)

AF:

0.00

AC:

AN:

35670

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37420

Middle Eastern (MID)

AF:

0.000244

AC:

AN:

4092

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078036

Other (OTH)

AF:

0.00

AC:

AN:

57660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Cholestanol storage disease

Uncertain:1

May 25, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.18

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.33

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.67

PhyloP100

0.29

PROVEAN

Benign

-0.76

REVEL

Uncertain

0.44

Sift

Uncertain

0.014

Sift4G

Uncertain

0.034

Polyphen

0.30

Vest4

0.34

MutPred

0.96

Loss of disorder (P = 0.0432);

MVP

0.65

ClinPred

0.065

GERP RS

2.7

PromoterAI

-0.18

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.45

gMVP

0.69

Mutation Taster

=12/188

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

2-218782183-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over