Genetic Variant HSDL1:p.Pro135Arg (chr16-84130248-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031463.5(HSDL1):c.404C>G(p.Pro135Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 0.0000014 ( 0 hom. )

Consequence

HSDL1
NM_031463.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.77

Publications

0 publications found

Variant links:

Genes affected

HSDL1 (HGNC:16475): (hydroxysteroid dehydrogenase like 1) Predicted to enable oxidoreductase activity. Located in intermediate filament cytoskeleton and mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

HSDL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21693262).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSDL1	NM_031463.5 link	c.404C>G	p.Pro135Arg	missense_variant	Exon 4 of 6	ENST00000219439.9	NP_113651.4	Q3SXM5-1I6L975
HSDL1	XM_005256189.4 link	c.404C>G	p.Pro135Arg	missense_variant	Exon 4 of 6		XP_005256246.1	Q3SXM5-1
HSDL1	NM_001146051.2 link	c.316-77C>G		intron_variant	Intron 4 of 6		NP_001139523.1	Q3SXM5-2I6L975

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSDL1	ENST00000219439.9 link	c.404C>G	p.Pro135Arg	missense_variant	Exon 4 of 6	1	NM_031463.5	ENSP00000219439.4	Q3SXM5-1
HSDL1	ENST00000434463.7 link	c.316-77C>G		intron_variant	Intron 4 of 6	2		ENSP00000407437.3	Q3SXM5-2
HSDL1	ENST00000568857.5 link	c.*71C>G		downstream_gene_variant		4		ENSP00000457026.1	H3BT52
HSDL1	ENST00000562224.1 link	c.*80C>G		downstream_gene_variant		4		ENSP00000455797.1	H3BQI7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 29, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.404C>G (p.P135R) alteration is located in exon 4 (coding exon 2) of the HSDL1 gene. This alteration results from a C to G substitution at nucleotide position 404, causing the proline (P) at amino acid position 135 to be replaced by an arginine (R). 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

0.11

BayesDel_addAF

Benign

0.0044

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.078

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.72

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.55

M_CAP

Benign

0.035

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-0.56

PhyloP100

3.8

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.98

REVEL

Uncertain

0.32

Sift

Benign

0.37

Sift4G

Benign

0.52

Polyphen

0.0

Vest4

0.32

MutPred

0.54

Loss of catalytic residue at L134 (P = 0.2607);

MVP

0.55

MPC

0.026

ClinPred

0.24

GERP RS

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.035

gMVP

0.78

Mutation Taster

=82/18

polymorphism

(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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16-84130248-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over