rs143879080

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_000781.3(CYP11A1):c.650A>C(p.Glu217Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00131 in 1,613,888 control chromosomes in the GnomAD database, including 3 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 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 2 hom. )

Consequence

CYP11A1
NM_000781.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.67

Publications

5 publications found

Variant links:

Genes affected

CYP11A1 (HGNC:2590): (cytochrome P450 family 11 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 protein localizes to the mitochondrial inner membrane and catalyzes the conversion of cholesterol to pregnenolone, the first and rate-limiting step in the synthesis of the steroid hormones. Two transcript variants encoding different isoforms have been found for this gene. The cellular location of the smaller isoform is unclear since it lacks the mitochondrial-targeting transit peptide. [provided by RefSeq, Jul 2008]

CYP11A1 Gene-Disease associations (from GenCC):

Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYP11A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP6

Variant 15-74343968-T-G is Benign according to our data. Variant chr15-74343968-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 434877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000781.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11A1	NM_000781.3	MANE Select	c.650A>C	p.Glu217Ala	missense	Exon 4 of 9	NP_000772.2	P05108-1
	CYP11A1	NM_001099773.2		c.176A>C	p.Glu59Ala	missense	Exon 4 of 9	NP_001093243.1	P05108-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP11A1	ENST00000268053.11	TSL:1 MANE Select	c.650A>C	p.Glu217Ala	missense	Exon 4 of 9	ENSP00000268053.6	P05108-1
CYP11A1	ENST00000950903.1		c.650A>C	p.Glu217Ala	missense	Exon 4 of 10	ENSP00000620962.1
CYP11A1	ENST00000950905.1		c.650A>C	p.Glu217Ala	missense	Exon 4 of 9	ENSP00000620964.1

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

197

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000567

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00269

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.00158

AC:

396

AN:

251164

AF XY:

0.00158

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.000795

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000879

Gnomad NFE exome

AF:

0.00310

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00132

AC:

1923

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

952

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33478

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000650

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00140

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00155

AC:

1729

AN:

1112004

Other (OTH)

AF:

0.00146

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

111

222

334

445

556

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00130

AC:

197

AN:

152062

Hom.:

Cov.:

AF XY:

0.000955

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41490

American (AMR)

AF:

0.0000655

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.000567

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00269

AC:

183

AN:

67980

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00208

Hom.:

Bravo

AF:

0.000986

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00208

AC:

253

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.00142

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency (1)

CYP11A1-related disorder (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

Eigen

Benign

0.14

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.027

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.8

PhyloP100

4.7

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.36

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.043

Polyphen

0.39

Vest4

0.18

MVP

0.92

MPC

0.41

ClinPred

0.063

GERP RS

4.2

Varity_R

0.80

gMVP

0.74

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.43

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.43

Position offset: -8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over