19-5685022-G-C

Variant names:

• chr19-5685022-G-C
• rs1483902768
• NM_198706.3:c.107G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_198706.3(HSD11B1L):​c.107G>C​(p.Gly36Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000698 in 1,432,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G36E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: HSD11B1L NM_198706.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.05
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198706.3. 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
	HSD11B1L	NM_198706.3	MANE Select	c.107G>C	p.Gly36Ala	missense	Exon 3 of 8	NP_941995.1	Q7Z5J1-2
	HSD11B1L	NM_001267868.2		c.248G>C	p.Gly83Ala	missense	Exon 4 of 9	NP_001254797.1	A0A087WWR3
	HSD11B1L	NM_198533.3		c.107G>C	p.Gly36Ala	missense	Exon 3 of 8	NP_940935.1	Q7Z5J1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD11B1L	ENST00000339423.7	TSL:1 MANE Select	c.107G>C	p.Gly36Ala	missense	Exon 3 of 8	ENSP00000340436.2	Q7Z5J1-2
	HSD11B1L	ENST00000423665.6	TSL:1	c.107G>C	p.Gly36Ala	missense	Exon 3 of 8	ENSP00000407154.2	Q7Z5J1-1
	HSD11B1L	ENST00000581773.5	TSL:1	c.107G>C	p.Gly36Ala	missense	Exon 4 of 9	ENSP00000462975.1	Q7Z5J1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432746 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 710534

African (AFR) AF: 0.00 AC: 0 AN: 32746

American (AMR) AF: 0.00 AC: 0 AN: 39338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25664

East Asian (EAS) AF: 0.00 AC: 0 AN: 37808

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097468

Other (OTH) AF: 0.00 AC: 0 AN: 59290

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.85
MutPred		0.96		Loss of disorder (P = 0.1777)
MVP		0.93
MPC		1.7
ClinPred		0.99	D
GERP RS		3.7
PromoterAI		0.0074	Neutral
Varity_R		0.77
gMVP		0.91
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1483902768; hg19: chr19-5685033;