1-209734349-C-T

Position:

• chr1-209734349-C-T

Variant summary

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

The ENST00000367027.5(HSD11B1):​c.707C>T​(p.Ala236Val) 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. 13/21 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 ENST00000367027.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.32

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25655264).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD11B1	NM_005525.4	c.707C>T	p.Ala236Val	missense_variant	6/6	ENST00000367027.5	NP_005516.1
HSD11B1-AS1	NR_134510.1	n.66+8148G>A		intron_variant, non_coding_transcript_variant
HSD11B1	NM_001206741.2	c.707C>T	p.Ala236Val	missense_variant	7/7		NP_001193670.1
HSD11B1	NM_181755.3	c.707C>T	p.Ala236Val	missense_variant	7/7		NP_861420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD11B1	ENST00000367027.5	c.707C>T	p.Ala236Val	missense_variant	6/6	1	NM_005525.4	ENSP00000355994	P1
HSD11B1	ENST00000367028.6	c.707C>T	p.Ala236Val	missense_variant	7/7	5		ENSP00000355995	P1
HSD11B1	ENST00000261465.5	c.707C>T	p.Ala236Val	missense_variant	7/7	5		ENSP00000261465

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jun 10, 2022

The c.707C>T (p.A236V) alteration is located in exon 6 (coding exon 6) of the HSD11B1 gene. This alteration results from a C to T substitution at nucleotide position 707, causing the alanine (A) at amino acid position 236 to be replaced by a valine (V). 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	0.18
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.81	T;T;.
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	0.95	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.14
MutPred		0.44		Loss of ubiquitination at K238 (P = 0.0531);Loss of ubiquitination at K238 (P = 0.0531);Loss of ubiquitination at K238 (P = 0.0531);
MVP		0.48
MPC		0.26
ClinPred		0.91	D
GERP RS		5.0
Varity_R		0.29
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-209907694;