chr1-209732427-G-A

Position:

• chr1-209732427-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005525.4(HSD11B1):​c.518-9G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,992 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0084 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (14 hom.)
• Consequence: HSD11B1 NM_005525.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001442
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.938

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-209732427-G-A is Benign according to our data. Variant chr1-209732427-G-A is described in ClinVar as [Benign]. Clinvar id is 787221.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00841 (1281/152256) while in subpopulation AFR AF= 0.028 (1164/41536). AF 95% confidence interval is 0.0267. There are 12 homozygotes in gnomad4. There are 599 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1281 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD11B1	NM_005525.4	c.518-9G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000367027.5	NP_005516.1
HSD11B1-AS1	NR_134510.1	n.66+10070C>T		intron_variant, non_coding_transcript_variant
HSD11B1	NM_001206741.2	c.518-9G>A		splice_polypyrimidine_tract_variant, intron_variant			NP_001193670.1
HSD11B1	NM_181755.3	c.518-9G>A		splice_polypyrimidine_tract_variant, intron_variant			NP_861420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD11B1	ENST00000367027.5	c.518-9G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005525.4	ENSP00000355994	P1
HSD11B1	ENST00000261465.5	c.518-9G>A		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000261465
HSD11B1	ENST00000367028.6	c.518-9G>A		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000355995	P1
HSD11B1	ENST00000615289.4	c.518-9G>A		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000478430

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1285 AN: 152138 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00263 AC: 661 AN: 251320 Hom.: 10 AF XY: 0.00194 AC XY: 264 AN XY: 135834

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00287

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00105 AC: 1534 AN: 1461736 Hom.: 14 Cov.: 32 AF XY: 0.000942 AC XY: 685 AN XY: 727166

Gnomad4 AFR exome AF: 0.0273

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00192

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000188

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.00841 AC: 1281 AN: 152256 Hom.: 12 Cov.: 32 AF XY: 0.00804 AC XY: 599 AN XY: 74476

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00431 Hom.: 3

Bravo AF: 0.00936

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.8
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0020
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: rs114140541; hg19: chr1-209905772;