chr17-35148376-A-G

Position:

• chr17-35148376-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001267052.2(UNC45B):​c.113A>G​(p.Asp38Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UNC45B NM_001267052.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.08

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24558261).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC45B	NM_001267052.2	c.113A>G	p.Asp38Gly	missense_variant	2/20	ENST00000394570.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC45B	ENST00000394570.7	c.113A>G	p.Asp38Gly	missense_variant	2/20	1	NM_001267052.2	P4
UNC45B	ENST00000591048.2	c.113A>G	p.Asp38Gly	missense_variant	1/17	1
UNC45B	ENST00000268876.9	c.113A>G	p.Asp38Gly	missense_variant	2/20	5		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

UNC45B: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	0.0022	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;.
Eigen	Benign	0.0071
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D;D;.
REVEL	Benign	0.16
Sift	Uncertain	0.029	D;D;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.014	B;P;B
Vest4		0.47
MutPred		0.37		Gain of MoRF binding (P = 0.032);Gain of MoRF binding (P = 0.032);Gain of MoRF binding (P = 0.032);
MVP		0.78
MPC		0.14
ClinPred		0.75	D
GERP RS		4.8
Varity_R		0.31
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1567751681; hg19: chr17-33475395;