17-35148430-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001267052.2(UNC45B):c.167C>T(p.Thr56Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,613,422 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (5 hom.)
• Consequence: UNC45B NM_001267052.2 missense, splice_region
• Scores: Splicing: ADA: 0.01321
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.316

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007403046).
• BP6: Variant 17-35148430-C-T is Benign according to our data. Variant chr17-35148430-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2360884.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC45B	NM_001267052.2	c.167C>T	p.Thr56Met	missense_variant, splice_region_variant	2/20	ENST00000394570.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC45B	ENST00000394570.7	c.167C>T	p.Thr56Met	missense_variant, splice_region_variant	2/20	1	NM_001267052.2	P4
UNC45B	ENST00000591048.2	c.167C>T	p.Thr56Met	missense_variant, splice_region_variant	1/17	1
UNC45B	ENST00000268876.9	c.167C>T	p.Thr56Met	missense_variant, splice_region_variant	2/20	5		A1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000455 AC: 113 AN: 248484 Hom.: 1 AF XY: 0.000601 AC XY: 81 AN XY: 134688

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00357

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000204 AC: 298 AN: 1461174 Hom.: 5 Cov.: 31 AF XY: 0.000271 AC XY: 197 AN XY: 726852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00321

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74444

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.000478 AC: 58

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.026	T;.;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0074	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.18	N;N;N
MutationTaster	Benign	0.89	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	2.0	N;N;.
REVEL	Benign	0.076
Sift	Benign	0.088	T;T;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.11
MutPred		0.49		Loss of ubiquitination at K55 (P = 0.0702);Loss of ubiquitination at K55 (P = 0.0702);Loss of ubiquitination at K55 (P = 0.0702);
MVP		0.38
MPC		0.10
ClinPred		0.021	T
GERP RS		-5.4
Varity_R		0.024
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.013
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.10		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: rs576792252; hg19: chr17-33475449;