8-142872521-A-C

Variant names:

• chr8-142872521-A-C
• rs4736312
• NM_000497.4:c.*1852T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000497.4(CYP11B1):​c.*1852T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 152,068 control chromosomes in the GnomAD database, including 28,989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28989 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: CYP11B1 NM_000497.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.259
• Publications: 12 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 8-142872521-A-C is Benign according to our data. Variant chr8-142872521-A-C is described in ClinVar as [Benign]. Clinvar id is 362104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11B1	NM_000497.4	c.*1852T>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000292427.10	NP_000488.3
CYP11B1	NM_001026213.1	c.*1852T>G		3_prime_UTR_variant	Exon 8 of 8		NP_001021384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP11B1	ENST00000292427.10	c.*1852T>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_000497.4	ENSP00000292427.5
CYP11B1	ENST00000519285.5	c.*1852T>G		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000430144.1
CYP11B1	ENST00000314111.4	n.3561T>G		non_coding_transcript_exon_variant	Exon 7 of 7	5
GML	ENST00000522728.5	c.181+31296A>C		intron_variant	Intron 3 of 4	3		ENSP00000430799.1

Frequencies

GnomAD3 genomes AF: 0.614 AC: 93337 AN: 151948 Hom.: 28969 Cov.: 33

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.636

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.654

Gnomad NFE AF: 0.566

Gnomad OTH AF: 0.629

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.614 AC: 93407 AN: 152068 Hom.: 28989 Cov.: 33 AF XY: 0.622 AC XY: 46259 AN XY: 74328

African (AFR) AF: 0.640 AC: 26539 AN: 41484

American (AMR) AF: 0.636 AC: 9718 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2246 AN: 3470

East Asian (EAS) AF: 0.848 AC: 4385 AN: 5174

South Asian (SAS) AF: 0.738 AC: 3559 AN: 4822

European-Finnish (FIN) AF: 0.613 AC: 6465 AN: 10552

Middle Eastern (MID) AF: 0.658 AC: 192 AN: 292

European-Non Finnish (NFE) AF: 0.566 AC: 38474 AN: 67976

Other (OTH) AF: 0.626 AC: 1320 AN: 2108

Alfa AF: 0.583 Hom.: 86284

Bravo AF: 0.613

Asia WGS AF: 0.728 AC: 2534 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of steroid 11-beta-monooxygenase Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Glucocorticoid-remediable aldosteronism Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.94
CADD	Benign	4.1
DANN	Benign	0.73
PhyloP100		-0.26

Splicing

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

Other links and lift over

dbSNP: rs4736312; hg19: chr8-143953937;