chr17-35148394-C-T

Variant names:

• chr17-35148394-C-T
• rs781198274
• NM_001267052.2:c.131C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001267052.2(UNC45B):​c.131C>T​(p.Thr44Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: UNC45B NM_001267052.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34594667).
• BS2: High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC45B	NM_001267052.2	c.131C>T	p.Thr44Met	missense_variant	Exon 2 of 20	ENST00000394570.7	NP_001253981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC45B	ENST00000394570.7	c.131C>T	p.Thr44Met	missense_variant	Exon 2 of 20	1	NM_001267052.2	ENSP00000378071.2
UNC45B	ENST00000591048.2	c.131C>T	p.Thr44Met	missense_variant	Exon 1 of 17	1		ENSP00000468335.1
UNC45B	ENST00000268876.9	c.131C>T	p.Thr44Met	missense_variant	Exon 2 of 20	5		ENSP00000268876.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152176 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

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250802 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135606

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727156

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.131C>T (p.T44M) alteration is located in exon 2 (coding exon 1) of the UNC45B gene. This alteration results from a C to T substitution at nucleotide position 131, causing the threonine (T) at amino acid position 44 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T;.;.
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.6	L;L;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.13	N;N;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.97	D;P;D
Vest4		0.41
MutPred		0.42		Gain of MoRF binding (P = 0.0846);Gain of MoRF binding (P = 0.0846);Gain of MoRF binding (P = 0.0846);
MVP		0.87
MPC		0.16
ClinPred		0.41	T
GERP RS		2.8
Varity_R		0.037
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs781198274; hg19: chr17-33475413;