15-90953003-G-A

Position:

chr15-90953003-G-A

Variant summary

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

The NM_018671.5(UNC45A):c.2378G>A(p.Arg793Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000596 in 1,613,514 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00057 ( 0 hom. )

Consequence

UNC45A
NM_018671.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.64

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:

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

RCCD1-AS1 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=0.010645449).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000873 (133/152280) while in subpopulation NFE AF= 0.00116 (79/68028). AF 95% confidence interval is 0.000955. There are 0 homozygotes in gnomad4. There are 65 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.2378G>A	p.Arg793Gln	missense_variant	18/20	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.2378G>A	p.Arg793Gln	missense_variant	18/20	1	NM_018671.5	ENSP00000407487.2		Q9H3U1-1

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.0253

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000614

AC:

154

AN:

250772

Hom.:

AF XY:

0.000716

AC XY:

AN XY:

135548

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000142

Gnomad NFE exome

AF:

0.000977

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000567

AC:

828

AN:

1461234

Hom.:

Cov.:

AF XY:

0.000585

AC XY:

425

AN XY:

726878

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000947

Gnomad4 NFE exome

AF:

0.000652

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000873

AC:

133

AN:

152280

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000926

Hom.:

Bravo

AF:

0.000997

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000634

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00180

EpiControl

AF:

0.00136

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 793 of the UNC45A protein (p.Arg793Gln). This variant is present in population databases (rs149872991, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. 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: 1422171). 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

0.15

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.055

.;.;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.0051

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

.;.;L

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.2

N;.;N

REVEL

Benign

0.071

Sift

Benign

0.38

T;.;T

Sift4G

Benign

0.60

T;.;T

Polyphen

0.91

.;.;P

Vest4

0.15

MVP

0.62

MPC

0.15

ClinPred

0.024

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.064

gMVP

0.42

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