15-90932510-C-T

Variant names:

• chr15-90932510-C-T
• rs752086762
• NM_001286451.2:c.31G>A

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

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]

ACMG classification

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
HDDC3	NM_001286451.2	c.31G>A	p.Ala11Thr	missense_variant	Exon 1 of 4	ENST00000394272.8	NP_001273380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDDC3	ENST00000394272.8	c.31G>A	p.Ala11Thr	missense_variant	Exon 1 of 4	2	NM_001286451.2	ENSP00000377814.4

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

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

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

Other links and lift over

dbSNP: rs752086762; hg19: chr15-91475740;