8-142875277-G-T

Variant names:

• chr8-142875277-G-T
• rs4541
• NM_000497.4:c.1157C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP2 BP4

The NM_000497.4(CYP11B1):​c.1157C>A​(p.Ala386Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,460,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A386V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: CYP11B1 NM_000497.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.420
• Publications: 26 publications found

Genes affected

CYP11B1 (HGNC:2591): (cytochrome P450 family 11 subfamily B 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 is involved in the conversion of progesterone to cortisol in the adrenal cortex. Mutations in this gene cause congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. Transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

GML (HGNC:4375): (glycosylphosphatidylinositol anchored molecule like) Predicted to be involved in DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; apoptotic process; and negative regulation of cell population proliferation. Predicted to be extrinsic component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000497.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: -1.5619 (below the threshold of 3.09). Trascript score misZ: -0.26962 (below the threshold of 3.09). GenCC associations: The gene is linked to glucocorticoid-remediable aldosteronism, congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35089636).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000497.4. 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
	CYP11B1	NM_000497.4	MANE Select	c.1157C>A	p.Ala386Glu	missense	Exon 7 of 9	NP_000488.3
	CYP11B1	NM_001026213.1		c.1157C>A	p.Ala386Glu	missense	Exon 7 of 8	NP_001021384.1	P15538-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	ENST00000292427.10	TSL:1 MANE Select	c.1157C>A	p.Ala386Glu	missense	Exon 7 of 9	ENSP00000292427.5	P15538-1
	CYP11B1	ENST00000377675.3	TSL:1	c.1370C>A	p.Ala457Glu	missense	Exon 9 of 11	ENSP00000366903.3	Q4VAR0
	CYP11B1	ENST00000517471.5	TSL:1	c.1157C>A	p.Ala386Glu	missense	Exon 7 of 8	ENSP00000428043.1	P15538-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000202 AC: 5 AN: 247626 AF XY: 0.0000298

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: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1460558 Hom.: 0 Cov.: 35 AF XY: 0.0000248 AC XY: 18 AN XY: 726590

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5474

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111686

Other (OTH) AF: 0.00 AC: 0 AN: 60304

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 13

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Deficiency of steroid 11-beta-monooxygenase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.85
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.42
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.16
Sift	Benign	0.035	D
Sift4G	Benign	0.066	T
Polyphen		0.46	P
Vest4		0.45
MutPred		0.69		Gain of disorder (P = 0.0969)
MVP		0.75
MPC		0.13
ClinPred		0.11	T
GERP RS		1.9
Varity_R		0.64
gMVP		0.96
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.030		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: rs4541; hg19: chr8-143956693;