Genetic Variant UNC45B:p.Arg49Trp (chr17-35148408-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2PP3_StrongBS2_Supporting

The NM_001267052.2(UNC45B):c.145C>T(p.Arg49Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

UNC45B
NM_001267052.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.654

Variant links:

Genes affected

UNC45B (HGNC:14304): (unc-45 myosin chaperone B) This gene encodes a co-chaperone required for folding and accumulation of type II myosins. The protein consists of three tetratricopeptide repeat motifs at the N-terminus that form a complex with heat shock protein 90, a central region of unknown function that is conserved in all Unc-45 proteins, and a C-terminal Unc-45/Cro1/She4 domain. The protein is expressed at high levels in striated muscle, where its muscle myosin chaperone activity is dependent on heat shock protein 90 acting as a co-chaperone. A missense mutation in this gene has been associated with cataract development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

UNC45B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

BS2

High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC45B	NM_001267052.2 link	c.145C>T	p.Arg49Trp	missense_variant	Exon 2 of 20	ENST00000394570.7	NP_001253981.1	Q8IWX7-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UNC45B	ENST00000394570.7 link	c.145C>T	p.Arg49Trp	missense_variant	Exon 2 of 20	1	NM_001267052.2	ENSP00000378071.2	Q8IWX7-3
UNC45B	ENST00000591048.2 link	c.145C>T	p.Arg49Trp	missense_variant	Exon 1 of 17	1		ENSP00000468335.1	Q8IWX7-2
UNC45B	ENST00000268876.9 link	c.145C>T	p.Arg49Trp	missense_variant	Exon 2 of 20	5		ENSP00000268876.4	Q8IWX7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250162

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135356

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.145C>T (p.R49W) alteration is located in exon 2 (coding exon 1) of the UNC45B gene. This alteration results from a C to T substitution at nucleotide position 145, causing the arginine (R) at amino acid position 49 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

D;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.48

MutationAssessor

Pathogenic

4.7

H;H;H

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.4

D;D;.

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.95

MutPred

0.90

Loss of methylation at R49 (P = 0.0462);Loss of methylation at R49 (P = 0.0462);Loss of methylation at R49 (P = 0.0462);

MVP

0.86

MPC

0.52

ClinPred

1.0

GERP RS

2.8

Varity_R

0.83

gMVP

0.80

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

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