15-90953156-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BS1_Supporting

The NM_018671.5(UNC45A):c.2423T>C(p.Val808Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000286 in 1,613,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V808V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

UNC45A
NM_018671.5 missense, splice_region

Scores

Splicing: ADA: 0.8618

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.13

Publications

7 publications found

Variant links:

Genes affected

UNC45A (HGNC:30594): (unc-45 myosin chaperone A) This gene encodes a regulatory component of the progesterone receptor/heat shock protein 90 chaperoning complex, which functions in the assembly and folding of the progesterone receptor. The encoded protein is thought to be essential for normal cell proliferation, and for the accumulation of myosin during development of muscle cells. [provided by RefSeq, Sep 2018]

UNC45A links:

RCCD1-AS1 (HGNC:54811): (RCCD1 and UNC45A antisense RNA 1)

RCCD1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3243098).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000299 (437/1461166) while in subpopulation NFE AF = 0.000385 (428/1111718). AF 95% confidence interval is 0.000355. There are 0 homozygotes in GnomAdExome4. There are 206 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018671.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UNC45A	NM_018671.5	MANE Select	c.2423T>C	p.Val808Ala	missense splice_region	Exon 19 of 20	NP_061141.2
UNC45A	NM_001323619.1		c.2423T>C	p.Val808Ala	missense splice_region	Exon 20 of 21	NP_001310548.1	Q9H3U1-1
UNC45A	NM_001039675.2		c.2378T>C	p.Val793Ala	missense splice_region	Exon 22 of 23	NP_001034764.1	Q9H3U1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UNC45A	ENST00000418476.2	TSL:1 MANE Select	c.2423T>C	p.Val808Ala	missense splice_region	Exon 19 of 20	ENSP00000407487.2	Q9H3U1-1
UNC45A	ENST00000639885.1	TSL:5	c.2843T>C	p.Val948Ala	missense splice_region	Exon 21 of 22	ENSP00000491150.1	A0A1W2PNX8
UNC45A	ENST00000936141.1		c.2510T>C	p.Val837Ala	missense splice_region	Exon 20 of 21	ENSP00000606200.1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000250

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000999

AC:

AN:

250360

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000204

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000299

AC:

437

AN:

1461166

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

206

AN XY:

726818

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53154

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000385

AC:

428

AN:

1111718

Other (OTH)

AF:

0.000133

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000158

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41460

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68026

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000267

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

M_CAP

Benign

0.035

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.1

PhyloP100

6.1

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.23

Sift

Benign

0.032

Sift4G

Uncertain

0.013

Polyphen

0.94

Vest4

0.92

MVP

0.58

MPC

0.62

ClinPred

0.34

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.20

gMVP

0.70

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.86

dbscSNV1_RF

Pathogenic

0.84

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over