chr17-35188145-A-C

Variant names:

• chr17-35188145-A-C
• rs11439
• NM_001267052.2:c.*1586A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001267052.2(UNC45B):​c.*1586A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0923 in 152,234 control chromosomes in the GnomAD database, including 816 homozygotes. 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 0.092 (816 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: UNC45B NM_001267052.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.552
• Publications: 5 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC45B	NM_001267052.2	c.*1586A>C		3_prime_UTR_variant	Exon 20 of 20	ENST00000394570.7	NP_001253981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC45B	ENST00000394570.7	c.*1586A>C		3_prime_UTR_variant	Exon 20 of 20	1	NM_001267052.2	ENSP00000378071.2
UNC45B	ENST00000268876.9	c.*1586A>C		3_prime_UTR_variant	Exon 20 of 20	5		ENSP00000268876.4

Frequencies

GnomAD3 genomes AF: 0.0922 AC: 14018 AN: 152116 Hom.: 812 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.0404

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0566

Gnomad OTH AF: 0.0918

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0923 AC: 14051 AN: 152234 Hom.: 816 Cov.: 32 AF XY: 0.0978 AC XY: 7284 AN XY: 74442

African (AFR) AF: 0.104 AC: 4310 AN: 41534

American (AMR) AF: 0.172 AC: 2636 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0404 AC: 140 AN: 3468

East Asian (EAS) AF: 0.209 AC: 1085 AN: 5186

South Asian (SAS) AF: 0.108 AC: 521 AN: 4824

European-Finnish (FIN) AF: 0.114 AC: 1208 AN: 10600

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0566 AC: 3848 AN: 68020

Other (OTH) AF: 0.0922 AC: 195 AN: 2114

Alfa AF: 0.0818 Hom.: 443

Bravo AF: 0.0968

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.4
DANN	Benign	0.64
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism (auto)

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: rs11439; hg19: chr17-33515164;