17-35148982-G-A

Position:

• chr17-35148982-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000394570.7(UNC45B):​c.178G>A​(p.Val60Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0481 in 1,613,820 control chromosomes in the GnomAD database, including 3,166 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.050 (334 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2832 hom.)
• Consequence: UNC45B ENST00000394570.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.91

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013712049).
• BP6: Variant 17-35148982-G-A is Benign according to our data. Variant chr17-35148982-G-A is described in ClinVar as [Benign]. Clinvar id is 1248888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC45B	NM_001267052.2	c.178G>A	p.Val60Ile	missense_variant	3/20	ENST00000394570.7	NP_001253981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC45B	ENST00000394570.7	c.178G>A	p.Val60Ile	missense_variant	3/20	1	NM_001267052.2	ENSP00000378071	P4
UNC45B	ENST00000591048.2	c.178G>A	p.Val60Ile	missense_variant	2/17	1		ENSP00000468335
UNC45B	ENST00000268876.9	c.178G>A	p.Val60Ile	missense_variant	3/20	5		ENSP00000268876	A1

Frequencies

GnomAD3 genomes AF: 0.0500 AC: 7598 AN: 152018 Hom.: 333 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0635

Gnomad SAS AF: 0.0912

Gnomad FIN AF: 0.0979

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0439

Gnomad OTH AF: 0.0421

GnomAD3 exomes AF: 0.0745 AC: 18720 AN: 251342 Hom.: 1352 AF XY: 0.0699 AC XY: 9489 AN XY: 135844

Gnomad AFR exome AF: 0.00997

Gnomad AMR exome AF: 0.216

Gnomad ASJ exome AF: 0.0163

Gnomad EAS exome AF: 0.0691

Gnomad SAS exome AF: 0.0870

Gnomad FIN exome AF: 0.0926

Gnomad NFE exome AF: 0.0405

Gnomad OTH exome AF: 0.0603

GnomAD4 exome AF: 0.0479 AC: 69981 AN: 1461684 Hom.: 2832 Cov.: 31 AF XY: 0.0485 AC XY: 35234 AN XY: 727162

Gnomad4 AFR exome AF: 0.00756

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.0617

Gnomad4 SAS exome AF: 0.0855

Gnomad4 FIN exome AF: 0.0908

Gnomad4 NFE exome AF: 0.0384

Gnomad4 OTH exome AF: 0.0451

GnomAD4 genome AF: 0.0500 AC: 7611 AN: 152136 Hom.: 334 Cov.: 32 AF XY: 0.0553 AC XY: 4115 AN XY: 74370

Gnomad4 AFR AF: 0.0116

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.0634

Gnomad4 SAS AF: 0.0909

Gnomad4 FIN AF: 0.0979

Gnomad4 NFE AF: 0.0440

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0445 Hom.: 522

Bravo AF: 0.0505

TwinsUK AF: 0.0372 AC: 138

ALSPAC AF: 0.0345 AC: 133

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.0381 AC: 328

ExAC AF: 0.0670 AC: 8132

Asia WGS AF: 0.0760 AC: 264 AN: 3478

EpiCase AF: 0.0360

EpiControl AF: 0.0341

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.050	T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.73	T;T;T
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.62	N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.62	N;N;.
REVEL	Benign	0.063
Sift	Benign	0.13	T;T;.
Sift4G	Benign	0.23	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.053
MPC		0.079
ClinPred		0.0036	T
GERP RS		1.5
Varity_R		0.050
gMVP		0.072

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: rs16970659; hg19: chr17-33476001; COSMIC: COSV52093086;