16-84130356-C-T

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

2
6
11

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]

Genome browser will be placed here

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
HSDL1NM_031463.5 linkc.296G>A p.Arg99Gln missense_variant Exon 4 of 6 ENST00000219439.9 NP_113651.4 Q3SXM5-1I6L975
HSDL1NM_001146051.2 linkc.296G>A p.Arg99Gln missense_variant Exon 4 of 7 NP_001139523.1 Q3SXM5-2I6L975
HSDL1XM_005256189.4 linkc.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 Appris UniProt
HSDL1ENST00000219439.9 linkc.296G>A p.Arg99Gln missense_variant Exon 4 of 6 1 NM_031463.5 ENSP00000219439.4 Q3SXM5-1
HSDL1ENST00000434463.7 linkc.296G>A p.Arg99Gln missense_variant Exon 4 of 7 2 ENSP00000407437.3 Q3SXM5-2
HSDL1ENST00000568857.5 linkc.296G>A p.Arg99Gln missense_variant Exon 4 of 4 4 ENSP00000457026.1 H3BT52
HSDL1ENST00000562224.1 linkc.296G>A p.Arg99Gln missense_variant Exon 4 of 4 4 ENSP00000455797.1 H3BQI7

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152186
Hom.:
0
Cov.:
33
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:
3
AN:
251462
Hom.:
0
AF XY:
0.00
AC XY:
0
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:
10
AN:
1461864
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
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:
1
AN:
152186
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
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:
2

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
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
17
DANN
Benign
0.95
DEOGEN2
Uncertain
0.77
D;.;D;.
Eigen
Benign
-0.085
Eigen_PC
Benign
-0.28
FATHMM_MKL
Benign
0.12
N
LIST_S2
Uncertain
0.92
D;D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.89
D;D;D;D
MetaSVM
Uncertain
0.33
D
MutationAssessor
Pathogenic
3.9
H;H;.;.
PrimateAI
Benign
0.19
T
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
T
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.

Other links and lift over

dbSNP: rs747743787; hg19: chr16-84163961; API