15-90932482-C-A

Variant names:

• chr15-90932482-C-A
• rs544321005
• NM_001286451.2:c.59G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001286451.2(HDDC3):​c.59G>T​(p.Arg20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000865 in 1,155,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: HDDC3 NM_001286451.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.510
• Publications: 0 publications found

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]

UNC45A Gene-Disease associations (from GenCC):

• osteootohepatoenteric syndrome

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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=0.22309357).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286451.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDDC3	NM_001286451.2	MANE Select	c.59G>T	p.Arg20Leu	missense	Exon 1 of 4	NP_001273380.1	Q8N4P3-1
	HDDC3	NM_198527.4		c.59G>T	p.Arg20Leu	missense	Exon 1 of 4	NP_940929.1	Q8N4P3-2
	UNC45A	NM_001039675.2		c.-759-1495C>A		intron	N/A	NP_001034764.1	Q9H3U1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDDC3	ENST00000394272.8	TSL:2 MANE Select	c.59G>T	p.Arg20Leu	missense	Exon 1 of 4	ENSP00000377814.4	Q8N4P3-1
	HDDC3	ENST00000559898.5	TSL:1	c.59G>T	p.Arg20Leu	missense	Exon 1 of 3	ENSP00000454103.1	H0YNP9
	HDDC3	ENST00000330334.7	TSL:1	c.59G>T	p.Arg20Leu	missense	Exon 1 of 4	ENSP00000330721.3	Q8N4P3-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.65e-7 AC: 1 AN: 1155934 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 555416

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24358

American (AMR) AF: 0.00 AC: 0 AN: 11610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15558

East Asian (EAS) AF: 0.0000350 AC: 1 AN: 28590

South Asian (SAS) AF: 0.00 AC: 0 AN: 37456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3166

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 960942

Other (OTH) AF: 0.00 AC: 0 AN: 46592

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.18	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.51
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.068
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.042	D
Polyphen		0.41	B
Vest4		0.42
MutPred		0.48		Loss of MoRF binding (P = 0.0081)
MVP		0.50
MPC		0.52
ClinPred		0.96	D
GERP RS		3.1
PromoterAI		-0.34	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.56

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

Other links and lift over

dbSNP: rs544321005; hg19: chr15-91475712;