Genetic Variant NM_018671.5:c.2387C>T (chr15-90953012-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018671.5(UNC45A):c.2387C>T(p.Thr796Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.034 in 1,613,534 control chromosomes in the GnomAD database, including 1,542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Synonymous variant affecting the same amino acid position (i.e. T796T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.059 ( 438 hom., cov: 32)

Exomes 𝑓: 0.031 ( 1104 hom. )

Consequence

UNC45A
NM_018671.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.86

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028594434).

BP6

Variant 15-90953012-C-T is Benign according to our data. Variant chr15-90953012-C-T is described in ClinVar as [Benign]. Clinvar id is 1169416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC45A	NM_018671.5 link	c.2387C>T	p.Thr796Met	missense_variant	Exon 18 of 20	ENST00000418476.2	NP_061141.2	Q9H3U1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC45A	ENST00000418476.2 link	c.2387C>T	p.Thr796Met	missense_variant	Exon 18 of 20	1	NM_018671.5	ENSP00000407487.2		Q9H3U1-1

Frequencies

GnomAD3 genomes

AF:

0.0588

AC:

8952

AN:

152144

Hom.:

438

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0349

Gnomad ASJ

AF:

0.0403

Gnomad EAS

AF:

0.0235

Gnomad SAS

AF:

0.0591

Gnomad FIN

AF:

0.0189

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0302

Gnomad OTH

AF:

0.0616

GnomAD3 exomes

AF:

0.0393

AC:

9859

AN:

250792

Hom.:

316

AF XY:

0.0402

AC XY:

5453

AN XY:

135568

show subpopulations

Gnomad AFR exome

AF:

0.134

Gnomad AMR exome

AF:

0.0230

Gnomad ASJ exome

AF:

0.0434

Gnomad EAS exome

AF:

0.0204

Gnomad SAS exome

AF:

0.0631

Gnomad FIN exome

AF:

0.0185

Gnomad NFE exome

AF:

0.0310

Gnomad OTH exome

AF:

0.0375

GnomAD4 exome

AF:

0.0314

AC:

45907

AN:

1461272

Hom.:

1104

Cov.:

AF XY:

0.0326

AC XY:

23692

AN XY:

726896

show subpopulations

Gnomad4 AFR exome

AF:

0.138

Gnomad4 AMR exome

AF:

0.0248

Gnomad4 ASJ exome

AF:

0.0428

Gnomad4 EAS exome

AF:

0.0205

Gnomad4 SAS exome

AF:

0.0640

Gnomad4 FIN exome

AF:

0.0203

Gnomad4 NFE exome

AF:

0.0260

Gnomad4 OTH exome

AF:

0.0390

GnomAD4 genome

AF:

0.0589

AC:

8968

AN:

152262

Hom.:

438

Cov.:

AF XY:

0.0584

AC XY:

4349

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.132

Gnomad4 AMR

AF:

0.0349

Gnomad4 ASJ

AF:

0.0403

Gnomad4 EAS

AF:

0.0238

Gnomad4 SAS

AF:

0.0600

Gnomad4 FIN

AF:

0.0189

Gnomad4 NFE

AF:

0.0302

Gnomad4 OTH

AF:

0.0610

Alfa

AF:

0.0362

Hom.:

202

Bravo

AF:

0.0622

TwinsUK

AF:

0.0248

AC:

ALSPAC

AF:

0.0252

AC:

ESP6500AA

AF:

0.129

AC:

568

ESP6500EA

AF:

0.0302

AC:

260

ExAC

AF:

0.0430

AC:

5222

Asia WGS

AF:

0.0380

AC:

131

AN:

3478

EpiCase

AF:

0.0355

EpiControl

AF:

0.0328

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

.;.;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D

MetaRNN

Benign

0.0029

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

.;.;M

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.6

D;.;D

REVEL

Benign

0.27

Sift

Uncertain

0.0030

D;.;D

Sift4G

Uncertain

0.0050

D;.;D

Polyphen

1.0

.;.;D

Vest4

0.34

MPC

0.59

ClinPred

0.016

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.67

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