1-209705887-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_005525.4(HSD11B1):c.165G>A(p.Ala55=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000786 in 1,614,040 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00095 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (2 hom.)
• Consequence: HSD11B1 NM_005525.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.20

Genes affected

HSD11B1 (HGNC:5208): (hydroxysteroid 11-beta dehydrogenase 1) The protein encoded by this gene is a microsomal enzyme that catalyzes the conversion of the stress hormone cortisol to the inactive metabolite cortisone. In addition, the encoded protein can catalyze the reverse reaction, the conversion of cortisone to cortisol. Too much cortisol can lead to central obesity, and a particular variation in this gene has been associated with obesity and insulin resistance in children. Mutations in this gene and H6PD (hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase)) are the cause of cortisone reductase deficiency. Alternate splicing results in multiple transcript variants encoding the same protein.[provided by RefSeq, May 2011]

HSD11B1-AS1 (HGNC:54053): (HSD11B1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-209705887-G-A is Benign according to our data. Variant chr1-209705887-G-A is described in ClinVar as [Benign]. Clinvar id is 3048552.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.2 with no splicing effect.
• BS2: High AC in GnomAd at 145 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD11B1	NM_005525.4	c.165G>A	p.Ala55=	synonymous_variant	2/6	ENST00000367027.5
HSD11B1-AS1	NR_134510.1	n.66+36610C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD11B1	ENST00000367027.5	c.165G>A	p.Ala55=	synonymous_variant	2/6	1	NM_005525.4	P1
HSD11B1-AS1	ENST00000441672.1	n.96+18143C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000953 AC: 145 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00894

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00125 AC: 314 AN: 251132 Hom.: 1 AF XY: 0.00123 AC XY: 167 AN XY: 135704

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00850

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000769 AC: 1124 AN: 1461720 Hom.: 2 Cov.: 32 AF XY: 0.000730 AC XY: 531 AN XY: 727162

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00805

Gnomad4 NFE exome AF: 0.000584

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000952 AC: 145 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74478

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00894

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000543 Hom.: 0

Bravo AF: 0.000283

EpiCase AF: 0.000218

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HSD11B1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	9.1
Dann	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs146919819; hg19: chr1-209879232; COSMIC: COSV99808334;