17-35148131-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001267052.2(UNC45B):c.1-133G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 985,236 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (41 hom.)
• Consequence: UNC45B NM_001267052.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.256

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-35148131-G-A is Benign according to our data. Variant chr17-35148131-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1214292.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0105 (1593/152250) while in subpopulation EAS AF= 0.0387 (200/5170). AF 95% confidence interval is 0.0343. There are 31 homozygotes in gnomad4. There are 808 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1585 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC45B	NM_001267052.2	c.1-133G>A		intron_variant		ENST00000394570.7
UNC45B	NM_001033576.2	c.-3-130G>A		intron_variant
UNC45B	XM_017024234.2	c.1-133G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC45B	ENST00000394570.7	c.1-133G>A		intron_variant		1	NM_001267052.2	P4
UNC45B	ENST00000268876.9	c.-3-130G>A		intron_variant		5		A1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1585 AN: 152132 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.0384

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00670

GnomAD4 exome AF: 0.00356 AC: 2968 AN: 832986 Hom.: 41 AF XY: 0.00392 AC XY: 1655 AN XY: 422094

Gnomad4 AFR exome AF: 0.0281

Gnomad4 AMR exome AF: 0.00372

Gnomad4 ASJ exome AF: 0.00426

Gnomad4 EAS exome AF: 0.0333

Gnomad4 SAS exome AF: 0.0121

Gnomad4 FIN exome AF: 0.0000225

Gnomad4 NFE exome AF: 0.000387

Gnomad4 OTH exome AF: 0.00564

GnomAD4 genome AF: 0.0105 AC: 1593 AN: 152250 Hom.: 31 Cov.: 32 AF XY: 0.0109 AC XY: 808 AN XY: 74442

Gnomad4 AFR AF: 0.0292

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.0387

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.0118

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.85
Dann	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs75935417; hg19: chr17-33475150;