NM_001267052.2:c.-1+107G>C

Variant names:

• chr17-35148017-G-C
• rs79383041
• NM_001267052.2:c.-1+107G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001267052.2(UNC45B):​c.-1+107G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 515,260 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (26 hom.)
• Consequence: UNC45B NM_001267052.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.220
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-35148017-G-C is Benign according to our data. Variant chr17-35148017-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1191774.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0105 (1597/152342) while in subpopulation EAS AF = 0.039 (202/5186). AF 95% confidence interval is 0.0346. There are 31 homozygotes in GnomAd4. There are 811 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AD,AR,Unknown gene

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+107G>C		intron	N/A	NP_001253981.1	Q8IWX7-3
	UNC45B	NM_001033576.2		c.-4+107G>C		intron	N/A	NP_001028748.1	Q8IWX7-3
	UNC45B	NM_173167.3		c.-247G>C		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+107G>C		intron	N/A	ENSP00000378071.2	Q8IWX7-3
	UNC45B	ENST00000958219.1		c.-23G>C		5_prime_UTR	Exon 1 of 20	ENSP00000628278.1
	UNC45B	ENST00000870786.1		c.-1+107G>C		intron	N/A	ENSP00000540845.1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1589 AN: 152224 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.0387

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00499 AC: 1812 AN: 362918 Hom.: 26 AF XY: 0.00535 AC XY: 1018 AN XY: 190212

African (AFR) AF: 0.0267 AC: 283 AN: 10584

American (AMR) AF: 0.00364 AC: 55 AN: 15102

Ashkenazi Jewish (ASJ) AF: 0.00399 AC: 45 AN: 11288

East Asian (EAS) AF: 0.0318 AC: 789 AN: 24780

South Asian (SAS) AF: 0.0113 AC: 410 AN: 36274

European-Finnish (FIN) AF: 0.0000431 AC: 1 AN: 23196

Middle Eastern (MID) AF: 0.00562 AC: 9 AN: 1600

European-Non Finnish (NFE) AF: 0.000498 AC: 109 AN: 218870

Other (OTH) AF: 0.00523 AC: 111 AN: 21224

GnomAD4 genome AF: 0.0105 AC: 1597 AN: 152342 Hom.: 31 Cov.: 32 AF XY: 0.0109 AC XY: 811 AN XY: 74498

African (AFR) AF: 0.0292 AC: 1216 AN: 41576

American (AMR) AF: 0.00359 AC: 55 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.0390 AC: 202 AN: 5186

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68024

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00804 Hom.: 1

Bravo AF: 0.0118

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.6
DANN	Benign	0.79
PhyloP100		-0.22
PromoterAI		-0.047	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs79383041; hg19: chr17-33475036;