1-209734386-G-C

Position:

• chr1-209734386-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005525.4(HSD11B1):​c.744G>C​(p.Gly248=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 1,614,094 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (25 hom.)
• Consequence: HSD11B1 NM_005525.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.384

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:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 1-209734386-G-C is Benign according to our data. Variant chr1-209734386-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 435467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.384 with no splicing effect.
• BS2: High AC in GnomAd4 at 409 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD11B1	NM_005525.4	c.744G>C	p.Gly248=	synonymous_variant	6/6	ENST00000367027.5
HSD11B1-AS1	NR_134510.1	n.66+8111C>G		intron_variant, non_coding_transcript_variant
HSD11B1	NM_001206741.2	c.744G>C	p.Gly248=	synonymous_variant	7/7
HSD11B1	NM_181755.3	c.744G>C	p.Gly248=	synonymous_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD11B1	ENST00000367027.5	c.744G>C	p.Gly248=	synonymous_variant	6/6	1	NM_005525.4	P1
HSD11B1	ENST00000367028.6	c.744G>C	p.Gly248=	synonymous_variant	7/7	5		P1
HSD11B1	ENST00000261465.5	c.744G>C	p.Gly248=	synonymous_variant	7/7	5

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 410 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00466

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00283 AC: 711 AN: 251030 Hom.: 1 AF XY: 0.00294 AC XY: 399 AN XY: 135634

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00477

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00476 AC: 6965 AN: 1461808 Hom.: 25 Cov.: 31 AF XY: 0.00464 AC XY: 3371 AN XY: 727202

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.00578

Gnomad4 OTH exome AF: 0.00382

GnomAD4 genome AF: 0.00269 AC: 409 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.00262 AC XY: 195 AN XY: 74462

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00466

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.00280

EpiCase AF: 0.00442

EpiControl AF: 0.00575

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 25, 2016

- -

HSD11B1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2019

This variant is classified as likely 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	-0.48
CADD	Benign	3.5
DANN	Benign	0.68

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: rs41283132; hg19: chr1-209907731;