17-35183460-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_001267052.2(UNC45B):c.2407C>T(p.Arg803Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,598,510 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R803Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

UNC45B
NM_001267052.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.51

Publications

5 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant 17-35183460-C-T is Pathogenic according to our data. Variant chr17-35183460-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 187851.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC45B	NM_001267052.2 link	c.2407C>T	p.Arg803Trp	missense_variant	Exon 19 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.2407C>T	p.Arg803Trp	missense_variant	Exon 19 of 20	1	NM_001267052.2	ENSP00000378071.2	Q8IWX7-3
UNC45B	ENST00000591048.2 link	c.2170C>T	p.Arg724Trp	missense_variant	Exon 16 of 17	1		ENSP00000468335.1	Q8IWX7-2
UNC45B	ENST00000268876.9 link	c.2413C>T	p.Arg805Trp	missense_variant	Exon 19 of 20	5		ENSP00000268876.4	Q8IWX7-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000623

AC:

AN:

240918

AF XY:

0.0000537

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000109

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000122

AC:

177

AN:

1446386

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

719408

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32944

American (AMR)

AF:

0.00

AC:

AN:

42730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25508

East Asian (EAS)

AF:

0.00

AC:

AN:

38876

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53038

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.000146

AC:

161

AN:

1104084

Other (OTH)

AF:

0.000235

AC:

AN:

59572

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Cataract 43

Pathogenic:1

Nov 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.97

D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

-0.083

MutationAssessor

Pathogenic

2.9

M;.;.

PhyloP100

1.5

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.4

D;.;.

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.94

MVP

0.89

MPC

0.50

ClinPred

0.93

GERP RS

1.8

Varity_R

0.83

gMVP

0.72

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over