rs370424081

Positions:

• chr17-35183460-C-G
• chr17-35183460-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The ENST00000394570.7(UNC45B):​c.2407C>G​(p.Arg803Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,446,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R803W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: UNC45B ENST00000394570.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-35183460-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 187851.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC45B	NM_001267052.2	c.2407C>G	p.Arg803Gly	missense_variant	19/20	ENST00000394570.7	NP_001253981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC45B	ENST00000394570.7	c.2407C>G	p.Arg803Gly	missense_variant	19/20	1	NM_001267052.2	ENSP00000378071	P4
UNC45B	ENST00000591048.2	c.2170C>G	p.Arg724Gly	missense_variant	16/17	1		ENSP00000468335
UNC45B	ENST00000268876.9	c.2413C>G	p.Arg805Gly	missense_variant	19/20	5		ENSP00000268876	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1446386 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2 AN XY: 719408

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	2.9	M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.5	D;.;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;P
Vest4		0.86
MutPred		0.66		Loss of ubiquitination at K807 (P = 0.0747);.;.;
MVP		0.80
MPC		0.37
ClinPred		0.99	D
GERP RS		1.8
Varity_R		0.81
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs370424081; hg19: chr17-33510479;