rs770579051

Variant names:

• chr17-35148382-C-A
• rs770579051
• NM_001267052.2:c.119C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-35148382-C-A
• chr17-35148382-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001267052.2(UNC45B):​c.119C>A​(p.Ala40Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: UNC45B NM_001267052.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18
• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16732556).

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.119C>A	p.Ala40Asp	missense	Exon 2 of 20	NP_001253981.1	Q8IWX7-3
	UNC45B	NM_173167.3		c.119C>A	p.Ala40Asp	missense	Exon 1 of 19	NP_775259.1	Q8IWX7-1
	UNC45B	NM_001033576.2		c.119C>A	p.Ala40Asp	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.119C>A	p.Ala40Asp	missense	Exon 2 of 20	ENSP00000378071.2	Q8IWX7-3
	UNC45B	ENST00000591048.2	TSL:1	c.119C>A	p.Ala40Asp	missense	Exon 1 of 17	ENSP00000468335.1	Q8IWX7-2
	UNC45B	ENST00000870786.1		c.119C>A	p.Ala40Asp	missense	Exon 2 of 21	ENSP00000540845.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000359 AC: 9 AN: 251036 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461776 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.24	N
PhyloP100		3.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.13
Sift	Benign	0.34	T
Sift4G	Benign	0.27	T
Polyphen		0.32	B
Vest4		0.40
MutPred		0.38		Gain of solvent accessibility (P = 0.0354)
MVP		0.83
MPC		0.16
ClinPred		0.17	T
GERP RS		2.8
PromoterAI		-0.070	Neutral
Varity_R		0.11
gMVP		0.45
Mutation Taster		=90/10	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: rs770579051; hg19: chr17-33475401;