Genetic Variant HSDL1:p.Arg99Gln (chr16-84130356-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_031463.5(HSDL1):c.296G>A(p.Arg99Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R99W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

HSDL1
NM_031463.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.308

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 made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSDL1	NM_031463.5 link	c.296G>A	p.Arg99Gln	missense_variant	Exon 4 of 6	ENST00000219439.9	NP_113651.4	Q3SXM5-1I6L975
HSDL1	NM_001146051.2 link	c.296G>A	p.Arg99Gln	missense_variant	Exon 4 of 7		NP_001139523.1	Q3SXM5-2I6L975
HSDL1	XM_005256189.4 link	c.296G>A	p.Arg99Gln	missense_variant	Exon 4 of 6		XP_005256246.1	Q3SXM5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSDL1	ENST00000219439.9 link	c.296G>A	p.Arg99Gln	missense_variant	Exon 4 of 6	1	NM_031463.5	ENSP00000219439.4	Q3SXM5-1
HSDL1	ENST00000434463.7 link	c.296G>A	p.Arg99Gln	missense_variant	Exon 4 of 7	2		ENSP00000407437.3	Q3SXM5-2
HSDL1	ENST00000568857.5 link	c.296G>A	p.Arg99Gln	missense_variant	Exon 4 of 4	4		ENSP00000457026.1	H3BT52
HSDL1	ENST00000562224.1 link	c.296G>A	p.Arg99Gln	missense_variant	Exon 4 of 4	4		ENSP00000455797.1	H3BQI7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251462

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.296G>A (p.R99Q) alteration is located in exon 4 (coding exon 2) of the HSDL1 gene. This alteration results from a G to A substitution at nucleotide position 296, causing the arginine (R) at amino acid position 99 to be replaced by a glutamine (Q). 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

0.13

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.77

D;.;D;.

Eigen

Benign

-0.085

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Pathogenic

3.9

H;H;.;.

PrimateAI

Benign

0.19

PROVEAN

Uncertain

-2.9

D;D;D;D

REVEL

Uncertain

0.40

Sift

Benign

0.092

T;T;T;T

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.76

P;.;.;.

Vest4

0.26

MutPred

0.92

Gain of ubiquitination at K103 (P = 0.0898);Gain of ubiquitination at K103 (P = 0.0898);Gain of ubiquitination at K103 (P = 0.0898);Gain of ubiquitination at K103 (P = 0.0898);

MVP

0.84

MPC

0.030

ClinPred

0.33

GERP RS

3.4

Varity_R

0.31

gMVP

0.63

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over