NM_001267052.2:c.1-133G>T

Variant names:

• chr17-35148131-G-T
• rs75935417
• NM_001267052.2:c.1-133G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001267052.2(UNC45B):​c.1-133G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000406 in 985,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: UNC45B NM_001267052.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.256
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

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.1-133G>T		intron	N/A	NP_001253981.1	Q8IWX7-3
	UNC45B	NM_001033576.2		c.-3-130G>T		intron	N/A	NP_001028748.1	Q8IWX7-3
	UNC45B	NM_173167.3		c.-133G>T		upstream_gene	N/A	NP_775259.1	Q8IWX7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC45B	ENST00000394570.7	TSL:1 MANE Select	c.1-133G>T		intron	N/A	ENSP00000378071.2	Q8IWX7-3
	UNC45B	ENST00000958208.1		c.-133G>T		5_prime_UTR	Exon 1 of 19	ENSP00000628267.1
	UNC45B	ENST00000870786.1		c.1-133G>T		intron	N/A	ENSP00000540845.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000240 AC: 2 AN: 833024 Hom.: 0 AF XY: 0.00000237 AC XY: 1 AN XY: 422110

African (AFR) AF: 0.00 AC: 0 AN: 19604

American (AMR) AF: 0.00 AC: 0 AN: 21526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16188

East Asian (EAS) AF: 0.00 AC: 0 AN: 33830

South Asian (SAS) AF: 0.00 AC: 0 AN: 55642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3404

European-Non Finnish (NFE) AF: 0.00000334 AC: 2 AN: 599620

Other (OTH) AF: 0.00 AC: 0 AN: 38684

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.63
DANN	Benign	0.50
PhyloP100		-0.26
PromoterAI		-0.0089	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs75935417; hg19: chr17-33475150;