1-209732479-G-T

Position:

• chr1-209732479-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_005525.4(HSD11B1):​c.561G>T​(p.Lys187Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSD11B1 NM_005525.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.91

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 1-209732479-G-T is Pathogenic according to our data. Variant chr1-209732479-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 31589.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD11B1	NM_005525.4	c.561G>T	p.Lys187Asn	missense_variant	5/6	ENST00000367027.5
HSD11B1-AS1	NR_134510.1	n.66+10018C>A		intron_variant, non_coding_transcript_variant
HSD11B1	NM_001206741.2	c.561G>T	p.Lys187Asn	missense_variant	6/7
HSD11B1	NM_181755.3	c.561G>T	p.Lys187Asn	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD11B1	ENST00000367027.5	c.561G>T	p.Lys187Asn	missense_variant	5/6	1	NM_005525.4	P1
HSD11B1	ENST00000367028.6	c.561G>T	p.Lys187Asn	missense_variant	6/7	5		P1
HSD11B1	ENST00000261465.5	c.561G>T	p.Lys187Asn	missense_variant	6/7	5
HSD11B1	ENST00000615289.4			downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cortisone reductase deficiency 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 08, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D;D;.
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.5	H;.;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.020	D;D;D
Sift4G	Uncertain	0.032	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.88
MutPred		0.79		Loss of methylation at K187 (P = 0.0096);Loss of methylation at K187 (P = 0.0096);Loss of methylation at K187 (P = 0.0096);
MVP		0.88
MPC		0.94
ClinPred		1.0	D
GERP RS		2.7
Varity_R		0.99
gMVP		0.99

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: rs756817759; hg19: chr1-209905824; COSMIC: COSV99807898; COSMIC: COSV99807898;