chr17-35148376-A-G

Variant names:

• chr17-35148376-A-G
• rs1567751681
• NM_001267052.2:c.113A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC45B	NM_001267052.2	MANE Select	c.113A>G	p.Asp38Gly	missense	Exon 2 of 20	NP_001253981.1	Q8IWX7-3
	UNC45B	NM_173167.3		c.113A>G	p.Asp38Gly	missense	Exon 1 of 19	NP_775259.1	Q8IWX7-1
	UNC45B	NM_001033576.2		c.113A>G	p.Asp38Gly	missense	Exon 2 of 20	NP_001028748.1	Q8IWX7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC45B	ENST00000394570.7	TSL:1 MANE Select	c.113A>G	p.Asp38Gly	missense	Exon 2 of 20	ENSP00000378071.2	Q8IWX7-3
	UNC45B	ENST00000591048.2	TSL:1	c.113A>G	p.Asp38Gly	missense	Exon 1 of 17	ENSP00000468335.1	Q8IWX7-2
	UNC45B	ENST00000870786.1		c.113A>G	p.Asp38Gly	missense	Exon 2 of 21	ENSP00000540845.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.16
Sift	Uncertain	0.029	D
Sift4G	Benign	0.13	T
Polyphen		0.014	B
Vest4		0.47
MutPred		0.37		Gain of MoRF binding (P = 0.032)
MVP		0.78
MPC		0.14
ClinPred		0.75	D
GERP RS		4.8
PromoterAI		-0.046	Neutral
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

Other links and lift over

dbSNP: rs1567751681; hg19: chr17-33475395;