chr17-35148131-G-A

Variant names:

• chr17-35148131-G-A
• rs75935417
• NM_001267052.2:c.1-133G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.256
• 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: Benign. The variant received -20 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 VariationId is 1214292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AD,AR,Unknown gene

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.1-133G>A		intron	N/A	NP_001253981.1	Q8IWX7-3
	UNC45B	NM_001033576.2		c.-3-130G>A		intron	N/A	NP_001028748.1	Q8IWX7-3
	UNC45B	NM_173167.3		c.-133G>A		upstream_gene	N/A	NP_775259.1	Q8IWX7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC45B	ENST00000394570.7	TSL:1 MANE Select	c.1-133G>A		intron	N/A	ENSP00000378071.2	Q8IWX7-3
	UNC45B	ENST00000958208.1		c.-133G>A		5_prime_UTR	Exon 1 of 19	ENSP00000628267.1
	UNC45B	ENST00000870786.1		c.1-133G>A		intron	N/A	ENSP00000540845.1

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

African (AFR) AF: 0.0281 AC: 551 AN: 19596

American (AMR) AF: 0.00372 AC: 80 AN: 21524

Ashkenazi Jewish (ASJ) AF: 0.00426 AC: 69 AN: 16184

East Asian (EAS) AF: 0.0333 AC: 1125 AN: 33820

South Asian (SAS) AF: 0.0121 AC: 671 AN: 55636

European-Finnish (FIN) AF: 0.0000225 AC: 1 AN: 44526

Middle Eastern (MID) AF: 0.00617 AC: 21 AN: 3404

European-Non Finnish (NFE) AF: 0.000387 AC: 232 AN: 599614

Other (OTH) AF: 0.00564 AC: 218 AN: 38682

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

African (AFR) AF: 0.0292 AC: 1215 AN: 41562

American (AMR) AF: 0.00366 AC: 56 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3466

East Asian (EAS) AF: 0.0387 AC: 200 AN: 5170

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68016

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00260 Hom.: 0

Bravo AF: 0.0118

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.85
DANN	Benign	0.50
PhyloP100		-0.26
PromoterAI		0.0074	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs75935417; hg19: chr17-33475150;