15-90932510-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001286451.2(HDDC3):​c.31G>A​(p.Ala11Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000374 in 1,149,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

HDDC3
NM_001286451.2 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.82
Variant links:
Genes affected
HDDC3 (HGNC:30522): (HD domain containing 3) Predicted to enable guanosine-3',5'-bis(diphosphate) 3'-diphosphatase activity. [provided by Alliance of Genome Resources, Apr 2022]
UNC45A (HGNC:30594): (unc-45 myosin chaperone A) This gene encodes a regulatory component of the progesterone receptor/heat shock protein 90 chaperoning complex, which functions in the assembly and folding of the progesterone receptor. The encoded protein is thought to be essential for normal cell proliferation, and for the accumulation of myosin during development of muscle cells. [provided by RefSeq, Sep 2018]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HDDC3NM_001286451.2 linkc.31G>A p.Ala11Thr missense_variant Exon 1 of 4 ENST00000394272.8 NP_001273380.1 Q8N4P3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HDDC3ENST00000394272.8 linkc.31G>A p.Ala11Thr missense_variant Exon 1 of 4 2 NM_001286451.2 ENSP00000377814.4 Q8N4P3-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000374
AC:
43
AN:
1149968
Hom.:
0
Cov.:
30
AF XY:
0.0000417
AC XY:
23
AN XY:
551404
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000877
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000438
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000113
ExAC
AF:
0.0000204
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 31, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.31G>A (p.A11T) alteration is located in exon 1 (coding exon 1) of the HDDC3 gene. This alteration results from a G to A substitution at nucleotide position 31, causing the alanine (A) at amino acid position 11 to be replaced by a threonine (T). 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
0.17
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.20
T;T;.;T
Eigen
Benign
0.051
Eigen_PC
Benign
0.22
FATHMM_MKL
Benign
0.75
D
LIST_S2
Uncertain
0.91
.;D;D;D
M_CAP
Benign
0.015
T
MetaRNN
Uncertain
0.54
D;D;D;D
MetaSVM
Benign
-0.79
T
MutationAssessor
Uncertain
2.6
M;M;M;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-1.4
N;.;N;N
REVEL
Benign
0.073
Sift
Benign
0.31
T;.;T;T
Sift4G
Benign
0.40
T;.;T;T
Polyphen
0.0050
B;B;B;.
Vest4
0.33
MutPred
0.62
Gain of phosphorylation at A11 (P = 0.0688);Gain of phosphorylation at A11 (P = 0.0688);Gain of phosphorylation at A11 (P = 0.0688);Gain of phosphorylation at A11 (P = 0.0688);
MVP
0.54
MPC
0.92
ClinPred
0.97
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.56
gMVP
0.54

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: rs752086762; hg19: chr15-91475740; API