8-142872956-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000497.4(CYP11B1):c.*1417G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 152,214 control chromosomes in the GnomAD database, including 1,342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1341 hom., cov: 33)
  • Exomes 𝑓: 0.13 (1 hom.)
• Consequence: CYP11B1 NM_000497.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.587

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 8-142872956-C-T is Benign according to our data. Variant chr8-142872956-C-T is described in ClinVar as [Benign]. Clinvar id is 362113.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP11B1	NM_000497.4	c.*1417G>A		3_prime_UTR_variant	9/9	ENST00000292427.10
CYP11B1	NM_001026213.1	c.*1417G>A		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP11B1	ENST00000292427.10	c.*1417G>A		3_prime_UTR_variant	9/9	1	NM_000497.4	P1
CYP11B1	ENST00000519285.5	c.*1417G>A		3_prime_UTR_variant	4/4	1
GML	ENST00000522728.5	c.181+31731C>T		intron_variant		3
CYP11B1	ENST00000314111.4	n.3126G>A		non_coding_transcript_exon_variant	7/7	5

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17485 AN: 152072 Hom.: 1336 Cov.: 33

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0660

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0931

Gnomad FIN AF: 0.0734

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.0849

Gnomad OTH AF: 0.105

GnomAD4 exome AF: 0.125 AC: 3 AN: 24 Hom.: 1 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 16

Gnomad4 ASJ exome AF: 0.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.0625

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.115 AC: 17511 AN: 152190 Hom.: 1341 Cov.: 33 AF XY: 0.112 AC XY: 8346 AN XY: 74424

Gnomad4 AFR AF: 0.215

Gnomad4 AMR AF: 0.0659

Gnomad4 ASJ AF: 0.0616

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0938

Gnomad4 FIN AF: 0.0734

Gnomad4 NFE AF: 0.0850

Gnomad4 OTH AF: 0.104

Alfa AF: 0.0974 Hom.: 152

Bravo AF: 0.117

Asia WGS AF: 0.0460 AC: 163 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of steroid 11-beta-monooxygenase Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Glucocorticoid-remediable aldosteronism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	3.8
Dann	Benign	0.27

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61752812; hg19: chr8-143954372;