chr15-90935356-C-T

Position:

chr15-90935356-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.32C>T(p.Pro11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000948 in 1,603,838 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 (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

UNC45A
NM_018671.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0250

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]

UNC45A links:

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=0.009537369).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000447 (68/152194) while in subpopulation AFR AF= 0.00154 (64/41536). AF 95% confidence interval is 0.00124. There are 0 homozygotes in gnomad4. There are 35 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/exons	MANE	Protein	UniProt
UNC45A	NM_018671.5 link	c.32C>T	p.Pro11Leu	missense_variant	1/20	ENST00000418476.2	NP_061141.2	Q9H3U1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC45A	ENST00000418476.2 link	c.32C>T	p.Pro11Leu	missense_variant	1/20	1	NM_018671.5	ENSP00000407487.2		Q9H3U1-1

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000131

AC:

AN:

221636

Hom.:

AF XY:

0.000106

AC XY:

AN XY:

122168

show subpopulations

Gnomad AFR exome

AF:

0.00173

Gnomad AMR exome

AF:

0.000182

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:

0.000185

GnomAD4 exome

AF:

0.0000579

AC:

AN:

1451644

Hom.:

Cov.:

AF XY:

0.0000485

AC XY:

AN XY:

721576

show subpopulations

Gnomad4 AFR exome

AF:

0.00183

Gnomad4 AMR exome

AF:

0.000274

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.000447

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.000261

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:

0.0000479

Hom.:

Bravo

AF:

0.000586

ESP6500AA

AF:

0.00233

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000108

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 27, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 11 of the UNC45A protein (p.Pro11Leu). This variant is present in population databases (rs202031609, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with UNC45A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1043563). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

0.084

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.51

M_CAP

Benign

0.012

MetaRNN

Benign

0.0095

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.6

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.86

REVEL

Benign

0.081

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.017

Polyphen

0.025

Vest4

0.29

MVP

0.30

MPC

0.13

ClinPred

0.067

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.13

gMVP

0.36

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over