NM_005525.4:c.608T>G

Variant names:

• chr1-209732526-T-G
• rs749071532
• NM_005525.4:c.608T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005525.4(HSD11B1):​c.608T>G​(p.Val203Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V203A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HSD11B1 NM_005525.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.25
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.95858 (below the threshold of 3.09). Trascript score misZ: 1.7211 (below the threshold of 3.09). GenCC associations: The gene is linked to cortisone reductase deficiency 2, cortisone reductase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16024712).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005525.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD11B1	NM_005525.4	MANE Select	c.608T>G	p.Val203Gly	missense	Exon 5 of 6	NP_005516.1	X5D2L1
	HSD11B1	NM_001206741.2		c.608T>G	p.Val203Gly	missense	Exon 6 of 7	NP_001193670.1	P28845
	HSD11B1	NM_181755.3		c.608T>G	p.Val203Gly	missense	Exon 6 of 7	NP_861420.1	P28845

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD11B1	ENST00000367027.5	TSL:1 MANE Select	c.608T>G	p.Val203Gly	missense	Exon 5 of 6	ENSP00000355994.3	P28845
	HSD11B1	ENST00000367028.6	TSL:5	c.608T>G	p.Val203Gly	missense	Exon 6 of 7	ENSP00000355995.1	P28845
	HSD11B1	ENST00000966146.1		c.605T>G	p.Val202Gly	missense	Exon 5 of 6	ENSP00000636205.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251356 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461652 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727154

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111808

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.3
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.052
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.11	T
Polyphen		0.031	B
Vest4		0.21
MutPred		0.37		Loss of stability (P = 0.0043)
MVP		0.12
MPC		0.31
ClinPred		0.53	D
GERP RS		3.1
Varity_R		0.48
gMVP		0.56
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs749071532; hg19: chr1-209905871;