rs143655263

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000781.3(CYP11A1):c.235G>A(p.Val79Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00496 in 1,614,158 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V79V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0052 ( 24 hom. )

Consequence

CYP11A1
NM_000781.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -1.83

Publications

10 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: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYP11A1 links:

ENSG00000261821 (HGNC:):

ENSG00000261821 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000781.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055402517).

BP6

Variant 15-74367351-C-T is Benign according to our data. Variant chr15-74367351-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 317132.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00297 (453/152270) while in subpopulation NFE AF = 0.00529 (360/68030). AF 95% confidence interval is 0.00484. There are 1 homozygotes in GnomAd4. There are 206 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 24 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.235G>A	p.Val79Ile	missense	Exon 1 of 9	NP_000772.2	P05108-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP11A1	ENST00000268053.11	TSL:1 MANE Select	c.235G>A	p.Val79Ile	missense	Exon 1 of 9	ENSP00000268053.6	P05108-1
CYP11A1	ENST00000950903.1		c.235G>A	p.Val79Ile	missense	Exon 1 of 10	ENSP00000620962.1
CYP11A1	ENST00000950905.1		c.235G>A	p.Val79Ile	missense	Exon 1 of 9	ENSP00000620964.1

Frequencies

GnomAD3 genomes

AF:

0.00298

AC:

454

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00529

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00276

AC:

695

AN:

251480

AF XY:

0.00260

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.00357

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00476

Gnomad OTH exome

AF:

0.00358

GnomAD4 exome

AF:

0.00517

AC:

7551

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00488

AC XY:

3548

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

33480

American (AMR)

AF:

0.00197

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00344

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000955

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00626

AC:

6959

AN:

1112008

Other (OTH)

AF:

0.00545

AC:

329

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

434

868

1301

1735

2169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

276

552

828

1104

1380

<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:

0.00297

AC:

453

AN:

152270

Hom.:

Cov.:

AF XY:

0.00277

AC XY:

206

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000794

AC:

AN:

41558

American (AMR)

AF:

0.00203

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000754

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00529

AC:

360

AN:

68030

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

109

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:

0.00429

Hom.:

Bravo

AF:

0.00337

EpiCase

AF:

0.00567

EpiControl

AF:

0.00379

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.43

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.082

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0047

LIST_S2

Benign

0.58

M_CAP

Benign

0.026

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

-1.8

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.48

REVEL

Benign

0.072

Sift

Benign

0.55

Sift4G

Benign

0.40

PromoterAI

-0.026

Neutral

(source)

Varity_R

0.13

gMVP

0.48

Mutation Taster

=88/12

polymorphism

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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