1-209706809-G-C

Position:

• chr1-209706809-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005525.4(HSD11B1):​c.320G>C​(p.Gly107Ala) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSD11B1 NM_005525.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24086285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD11B1	NM_005525.4	c.320G>C	p.Gly107Ala	missense_variant	3/6	ENST00000367027.5
HSD11B1-AS1	NR_134510.1	n.66+35688C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD11B1	ENST00000367027.5	c.320G>C	p.Gly107Ala	missense_variant	3/6	1	NM_005525.4	P1
HSD11B1-AS1	ENST00000441672.1	n.96+17221C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251256 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.320G>C (p.G107A) alteration is located in exon 3 (coding exon 3) of the HSD11B1 gene. This alteration results from a G to C substitution at nucleotide position 320, causing the glycine (G) at amino acid position 107 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.0020	T;T;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.70	T;T;T;.
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.79	.;N;.;N
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.35	.;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.24	.;T;T;T
Sift4G	Benign	0.97	T;T;T;T
Polyphen		0.82	.;P;.;P
Vest4		0.27, 0.27
MutPred		0.46		Loss of catalytic residue at A106 (P = 0.0858);Loss of catalytic residue at A106 (P = 0.0858);Loss of catalytic residue at A106 (P = 0.0858);Loss of catalytic residue at A106 (P = 0.0858);
MVP		0.61
MPC		0.26
ClinPred		0.40	T
GERP RS		3.2
Varity_R		0.30
gMVP		0.37

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: rs746362951; hg19: chr1-209880154;