17-35183460-C-T

Variant names:

• chr17-35183460-C-T
• rs370424081
• NM_001267052.2:c.2407C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PP3_Strong PP5 BS2_Supporting

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).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: UNC45B NM_001267052.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.51

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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 id is 187851.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-35183460-C-T is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAd4 at 15 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	c.2407C>T	p.Arg803Trp	missense_variant	Exon 19 of 20	ENST00000394570.7	NP_001253981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC45B	ENST00000394570.7	c.2407C>T	p.Arg803Trp	missense_variant	Exon 19 of 20	1	NM_001267052.2	ENSP00000378071.2
UNC45B	ENST00000591048.2	c.2170C>T	p.Arg724Trp	missense_variant	Exon 16 of 17	1		ENSP00000468335.1
UNC45B	ENST00000268876.9	c.2413C>T	p.Arg805Trp	missense_variant	Exon 19 of 20	5		ENSP00000268876.4

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152124 Hom.: 0 Cov.: 31

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

GnomAD3 exomes AF: 0.0000623 AC: 15 AN: 240918 Hom.: 0 AF XY: 0.0000537 AC XY: 7 AN XY: 130392

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 SAS exome AF: 0.0000345

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.: 0 Cov.: 30 AF XY: 0.000106 AC XY: 76 AN XY: 719408

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: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000146

Gnomad4 OTH exome AF: 0.000235

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152124 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74300

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.000144

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cataract 43 Pathogenic:1

Nov 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Pathogenic	2.9	M;.;.
PrimateAI	Uncertain	0.75	T
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	D
GERP RS		1.8
Varity_R		0.83
gMVP		0.72

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

Other links and lift over

dbSNP: rs370424081; hg19: chr17-33510479;