15-90952969-G-A

Variant names:

• chr15-90952969-G-A
• rs1295241064
• NM_018671.5:c.2344G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018671.5(UNC45A):​c.2344G>A​(p.Gly782Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UNC45A NM_018671.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12

Genes affected

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]

RCCD1-AS1 (HGNC:54811): (RCCD1 and UNC45A antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31701195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC45A	NM_018671.5	c.2344G>A	p.Gly782Ser	missense_variant	Exon 18 of 20	ENST00000418476.2	NP_061141.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC45A	ENST00000418476.2	c.2344G>A	p.Gly782Ser	missense_variant	Exon 18 of 20	1	NM_018671.5	ENSP00000407487.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 782 of the UNC45A protein (p.Gly782Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with UNC45A-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt UNC45A protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.026	.;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	.;.;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.64	N;.;N
REVEL	Benign	0.17
Sift	Benign	0.46	T;.;T
Sift4G	Benign	0.70	T;.;T
Polyphen		0.98	.;.;D
Vest4		0.21
MutPred		0.32		.;.;Gain of loop (P = 0.069);
MVP		0.61
MPC		0.13
ClinPred		0.64	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1295241064; hg19: chr15-91496199;