19-5687950-C-T

Variant names:

• chr19-5687950-C-T
• rs1020004431
• ENST00000423665.6:c.703C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198533.3(HSD11B1L):​c.703C>T​(p.Arg235Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: HSD11B1L NM_198533.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.15

Genes affected

HSD11B1L (HGNC:30419): (hydroxysteroid 11-beta dehydrogenase 1 like) This gene is a member of the hydroxysteroid dehydrogenase family. The encoded protein is similar to an enzyme that catalyzes the interconversion of inactive to active glucocorticoids (e.g. cortisone). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2012]

RPL36 (HGNC:13631): (ribosomal protein L36) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L36E family of ribosomal proteins. It is located in the cytoplasm. Transcript variants derived from alternative splicing exist; they encode the same protein. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06387365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD11B1L	NM_198706.3	c.*5C>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000339423.7	NP_941995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD11B1L	ENST00000339423.7	c.*5C>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_198706.3	ENSP00000340436.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000618 AC: 1 AN: 161894 Hom.: 0 AF XY: 0.0000115 AC XY: 1 AN XY: 87252

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000859

Gnomad SAS 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: 7.11e-7 AC: 1 AN: 1406574 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 694944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000276

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.703C>T (p.R235W) alteration is located in exon 8 (coding exon 7) of the HSD11B1L gene. This alteration results from a C to T substitution at nucleotide position 703, causing the arginine (R) at amino acid position 235 to be replaced by a tryptophan (W). 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	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	3.2
DANN	Benign	0.71
DEOGEN2	Benign	0.017	.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.51	T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.0	.;.;N
PROVEAN	Benign	-1.5	.;N;N
REVEL	Benign	0.23
Sift	Benign	0.044	.;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.0010	B;.;B
Vest4		0.058
MutPred		0.45		.;.;Loss of solvent accessibility (P = 0.0036);
MVP		0.26
MPC		0.83
ClinPred		0.077	T
GERP RS		-2.2
Varity_R		0.050

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: rs1020004431; hg19: chr19-5687961;