Genetic Variant NM_005525.4:c.332-29T>G (chr1-209706914-T-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005525.4(HSD11B1):c.332-29T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,611,884 control chromosomes in the GnomAD database, including 33,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 2972 hom., cov: 32)

Exomes 𝑓: 0.20 ( 30048 hom. )

Consequence

HSD11B1
NM_005525.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.07

Publications

42 publications found

Variant links:

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 links:

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

HSD11B1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 1-209706914-T-G is Benign according to our data. Variant chr1-209706914-T-G is described in ClinVar as Benign. ClinVar VariationId is 375729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HSD11B1	NM_005525.4	MANE Select	c.332-29T>G	intron	N/A	NP_005516.1	X5D2L1
HSD11B1	NM_001206741.2		c.332-29T>G	intron	N/A	NP_001193670.1	P28845
HSD11B1	NM_181755.3		c.332-29T>G	intron	N/A	NP_861420.1	P28845

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HSD11B1	ENST00000367027.5	TSL:1 MANE Select	c.332-29T>G	intron	N/A	ENSP00000355994.3	P28845
HSD11B1	ENST00000367028.6	TSL:5	c.332-29T>G	intron	N/A	ENSP00000355995.1	P28845
HSD11B1	ENST00000966146.1		c.332-32T>G	intron	N/A	ENSP00000636205.1

Frequencies

GnomAD3 genomes

AF:

0.196

AC:

29796

AN:

152074

Hom.:

2962

Cov.:

show subpopulations

Gnomad AFR

AF:

0.178

Gnomad AMI

AF:

0.196

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.210

Gnomad EAS

AF:

0.217

Gnomad SAS

AF:

0.169

Gnomad FIN

AF:

0.263

Gnomad MID

AF:

0.143

Gnomad NFE

AF:

0.201

Gnomad OTH

AF:

0.189

GnomAD2 exomes

AF:

0.206

AC:

51796

AN:

250856

AF XY:

0.205

show subpopulations

Gnomad AFR exome

AF:

0.178

Gnomad AMR exome

AF:

0.209

Gnomad ASJ exome

AF:

0.212

Gnomad EAS exome

AF:

0.230

Gnomad FIN exome

AF:

0.265

Gnomad NFE exome

AF:

0.204

Gnomad OTH exome

AF:

0.199

GnomAD4 exome

AF:

0.200

AC:

292303

AN:

1459692

Hom.:

30048

Cov.:

AF XY:

0.199

AC XY:

144603

AN XY:

726312

show subpopulations

African (AFR)

AF:

0.174

AC:

5809

AN:

33436

American (AMR)

AF:

0.208

AC:

9292

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.211

AC:

5520

AN:

26122

East Asian (EAS)

AF:

0.183

AC:

7259

AN:

39680

South Asian (SAS)

AF:

0.174

AC:

14963

AN:

86200

European-Finnish (FIN)

AF:

0.263

AC:

14033

AN:

53408

Middle Eastern (MID)

AF:

0.136

AC:

782

AN:

5764

European-Non Finnish (NFE)

AF:

0.200

AC:

222246

AN:

1110048

Other (OTH)

AF:

0.206

AC:

12399

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

14135

28270

42404

56539

70674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7736

15472

23208

30944

38680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.196

AC:

29838

AN:

152192

Hom.:

2972

Cov.:

AF XY:

0.197

AC XY:

14646

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.178

AC:

7397

AN:

41534

American (AMR)

AF:

0.176

AC:

2694

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.210

AC:

729

AN:

3466

East Asian (EAS)

AF:

0.217

AC:

1124

AN:

5178

South Asian (SAS)

AF:

0.168

AC:

812

AN:

4822

European-Finnish (FIN)

AF:

0.263

AC:

2787

AN:

10582

Middle Eastern (MID)

AF:

0.130

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.201

AC:

13675

AN:

68002

Other (OTH)

AF:

0.190

AC:

403

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1252

2504

3756

5008

6260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

330

660

990

1320

1650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.201

Hom.:

8365

Bravo

AF:

0.193

Asia WGS

AF:

0.208

AC:

724

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cortisone reductase deficiency 2 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

2.9

(source)

DANN

Benign

0.70

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over