15-90935355-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_018671.5(UNC45A):​c.31C>T​(p.Pro11Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000324 in 1,603,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

UNC45A
NM_018671.5 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.432
Variant links:
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.009123027).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000184 (28/152182) while in subpopulation AFR AF= 0.000674 (28/41532). AF 95% confidence interval is 0.000478. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
UNC45ANM_018671.5 linkc.31C>T p.Pro11Ser missense_variant Exon 1 of 20 ENST00000418476.2 NP_061141.2 Q9H3U1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
UNC45AENST00000418476.2 linkc.31C>T p.Pro11Ser missense_variant Exon 1 of 20 1 NM_018671.5 ENSP00000407487.2 Q9H3U1-1

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
152064
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000676
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000543
AC:
12
AN:
220902
Hom.:
0
AF XY:
0.0000657
AC XY:
8
AN XY:
121784
show subpopulations
Gnomad AFR exome
AF:
0.000871
Gnomad AMR exome
AF:
0.0000304
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS 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:
0.0000165
AC:
24
AN:
1451142
Hom.:
0
Cov.:
34
AF XY:
0.0000139
AC XY:
10
AN XY:
721272
show subpopulations
Gnomad4 AFR exome
AF:
0.000570
Gnomad4 AMR exome
AF:
0.0000229
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.000228
AC XY:
17
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.000674
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000356
Hom.:
0
Bravo
AF:
0.000246
ExAC
AF:
0.0000667
AC:
8

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Sep 01, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 11 of the UNC45A protein (p.Pro11Ser). This variant is present in population databases (rs572718253, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with UNC45A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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
0.072
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
16
DANN
Uncertain
0.98
DEOGEN2
Benign
0.022
T
Eigen
Benign
-0.46
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.095
N
LIST_S2
Benign
0.52
T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.0091
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.90
L
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-0.68
N
REVEL
Benign
0.082
Sift
Pathogenic
0.0
D
Sift4G
Benign
0.064
T
Polyphen
0.033
B
Vest4
0.13
MVP
0.29
MPC
0.13
ClinPred
0.062
T
GERP RS
3.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.18
gMVP
0.32

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: rs572718253; hg19: chr15-91478585; API