Genetic Variant UNC45B:p.Ala778Gly (chr17-35180636-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001267052.2(UNC45B):c.2333C>G(p.Ala778Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A778V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

UNC45B
NM_001267052.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.80

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

myofibrillar myopathy 11
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
cataract 43
Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset posterior subcapsular cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

UNC45B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.831

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267052.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UNC45B	NM_001267052.2	MANE Select	c.2333C>G	p.Ala778Gly	missense	Exon 18 of 20	NP_001253981.1	Q8IWX7-3
UNC45B	NM_173167.3		c.2339C>G	p.Ala780Gly	missense	Exon 17 of 19	NP_775259.1	Q8IWX7-1
UNC45B	NM_001033576.2		c.2333C>G	p.Ala778Gly	missense	Exon 18 of 20	NP_001028748.1	Q8IWX7-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UNC45B	ENST00000394570.7	TSL:1 MANE Select	c.2333C>G	p.Ala778Gly	missense	Exon 18 of 20	ENSP00000378071.2	Q8IWX7-3
UNC45B	ENST00000591048.2	TSL:1	c.2096C>G	p.Ala699Gly	missense	Exon 15 of 17	ENSP00000468335.1	Q8IWX7-2
UNC45B	ENST00000870786.1		c.2450C>G	p.Ala817Gly	missense	Exon 19 of 21	ENSP00000540845.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.067

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.14

MutationAssessor

Pathogenic

3.3

PhyloP100

7.8

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.51

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.80

MVP

0.86

MPC

0.50

ClinPred

0.99

GERP RS

5.2

Varity_R

0.52

gMVP

0.55

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over