15-90932482-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001286451.2(HDDC3):​c.59G>A​(p.Arg20Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 1,308,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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: 𝑓 0.0000066 (0 hom., 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01867807).

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>A	p.Arg20Gln	missense	Exon 1 of 4	NP_001273380.1	Q8N4P3-1
	HDDC3	NM_198527.4		c.59G>A	p.Arg20Gln	missense	Exon 1 of 4	NP_940929.1	Q8N4P3-2
	UNC45A	NM_001039675.2		c.-759-1495C>T		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>A	p.Arg20Gln	missense	Exon 1 of 4	ENSP00000377814.4	Q8N4P3-1
	HDDC3	ENST00000559898.5	TSL:1	c.59G>A	p.Arg20Gln	missense	Exon 1 of 3	ENSP00000454103.1	H0YNP9
	HDDC3	ENST00000330334.7	TSL:1	c.59G>A	p.Arg20Gln	missense	Exon 1 of 4	ENSP00000330721.3	Q8N4P3-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000313 AC: 1 AN: 31986 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.65e-7 AC: 1 AN: 1155934 Hom.: 0 Cov.: 30 AF XY: 0.00000180 AC XY: 1 AN XY: 555416

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: 0.00 AC: 0 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: 0.00000104 AC: 1 AN: 960942

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

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74514

African (AFR) AF: 0.00 AC: 0 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

ExAC AF: 0.00000941 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.51
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.027
Sift	Benign	0.043	D
Sift4G	Benign	0.12	T
Polyphen		0.013	B
Vest4		0.20
MutPred		0.40		Loss of MoRF binding (P = 0.0168)
MVP		0.35
MPC		0.36
ClinPred		0.18	T
GERP RS		3.1
PromoterAI		-0.084	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.34
Mutation Taster		=70/30	polymorphism

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;