rs532523562

Variant names:

• chr6-99443564-C-A
• rs532523562
• NM_001346022.3:c.2073+1G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001346022.3(USP45):​c.2073+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,600,952 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: USP45 NM_001346022.3 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.38
• Publications: 0 publications found

Genes affected

USP45 (HGNC:20080): (ubiquitin specific peptidase 45) The protein encoded by this gene is a deubiquitylase that binds ERCC1, the catalytic subunit of the XPF-ERCC1 DNA repair endonuclease. This endonuclease is a critical regulator of DNA repair processes, and the deubiquitylase activity of the encoded protein is important for maintaining the DNA repair ability of XPF-ERCC1. [provided by RefSeq, Sep 2016]

PNISR-AS1 (HGNC:40958): (PNISR antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346022.3. 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
	USP45	NM_001346022.3	MANE Select	c.2073+1G>T		splice_donor intron	N/A	NP_001332951.1	Q70EL2-1
	USP45	NM_001080481.3		c.2073+1G>T		splice_donor intron	N/A	NP_001073950.1	Q70EL2-1
	USP45	NM_001346021.3		c.2073+1G>T		splice_donor intron	N/A	NP_001332950.1	Q70EL2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP45	ENST00000500704.7	TSL:5 MANE Select	c.2073+1G>T		splice_donor intron	N/A	ENSP00000424372.1	Q70EL2-1
	USP45	ENST00000327681.10	TSL:1	c.2073+1G>T		splice_donor intron	N/A	ENSP00000333376.6	Q70EL2-1
	USP45	ENST00000496518.6	TSL:1	n.*1039+1G>T		splice_donor intron	N/A	ENSP00000421248.1	H0Y8J5

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000365 AC: 9 AN: 246440 AF XY: 0.0000601

Gnomad AFR exome AF: 0.00

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: 0.0000534

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000110 AC: 159 AN: 1448872 Hom.: 0 Cov.: 29 AF XY: 0.000101 AC XY: 73 AN XY: 720482

African (AFR) AF: 0.0000302 AC: 1 AN: 33154

American (AMR) AF: 0.00 AC: 0 AN: 43672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25796

East Asian (EAS) AF: 0.00 AC: 0 AN: 39450

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.000139 AC: 154 AN: 1105044

Other (OTH) AF: 0.0000501 AC: 3 AN: 59842

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74272

African (AFR) AF: 0.00 AC: 0 AN: 41396

American (AMR) AF: 0.0000656 AC: 1 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Leber congenital amaurosis (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	34
DANN	Benign	0.96
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.4
GERP RS		4.8
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 2
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs532523562; hg19: chr6-99891440;