6-99446062-T-C

Variant names:

• chr6-99446062-T-C
• rs4504482
• NM_001346022.3:c.1710A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001346022.3(USP45):​c.1710A>G​(p.Gly570Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,613,670 control chromosomes in the GnomAD database, including 77,351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.29 (6729 hom., cov: 32)
  • Exomes 𝑓: 0.31 (70622 hom.)
• Consequence: USP45 NM_001346022.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.186
• Publications: 27 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-99446062-T-C is Benign according to our data. Variant chr6-99446062-T-C is described in ClinVar as Benign. ClinVar VariationId is 1684199.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.186 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP45	NM_001346022.3	MANE Select	c.1710A>G	p.Gly570Gly	synonymous	Exon 14 of 18	NP_001332951.1
	USP45	NM_001080481.3		c.1710A>G	p.Gly570Gly	synonymous	Exon 14 of 18	NP_001073950.1
	USP45	NM_001346021.3		c.1710A>G	p.Gly570Gly	synonymous	Exon 14 of 18	NP_001332950.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP45	ENST00000500704.7	TSL:5 MANE Select	c.1710A>G	p.Gly570Gly	synonymous	Exon 14 of 18	ENSP00000424372.1
	USP45	ENST00000327681.10	TSL:1	c.1710A>G	p.Gly570Gly	synonymous	Exon 14 of 18	ENSP00000333376.6
	USP45	ENST00000496518.6	TSL:1	n.*676A>G		non_coding_transcript_exon	Exon 9 of 13	ENSP00000421248.1

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44334 AN: 151942 Hom.: 6735 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.309

GnomAD2 exomes AF: 0.339 AC: 85045 AN: 250724 AF XY: 0.343

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.384

Gnomad ASJ exome AF: 0.358

Gnomad EAS exome AF: 0.511

Gnomad FIN exome AF: 0.298

Gnomad NFE exome AF: 0.299

Gnomad OTH exome AF: 0.333

GnomAD4 exome AF: 0.306 AC: 447507 AN: 1461610 Hom.: 70622 Cov.: 48 AF XY: 0.309 AC XY: 224829 AN XY: 727106

African (AFR) AF: 0.236 AC: 7916 AN: 33474

American (AMR) AF: 0.381 AC: 17034 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 9191 AN: 26130

East Asian (EAS) AF: 0.427 AC: 16968 AN: 39696

South Asian (SAS) AF: 0.412 AC: 35561 AN: 86244

European-Finnish (FIN) AF: 0.305 AC: 16248 AN: 53250

Middle Eastern (MID) AF: 0.387 AC: 2233 AN: 5768

European-Non Finnish (NFE) AF: 0.290 AC: 322872 AN: 1111944

Other (OTH) AF: 0.323 AC: 19484 AN: 60388

GnomAD4 genome AF: 0.292 AC: 44339 AN: 152060 Hom.: 6729 Cov.: 32 AF XY: 0.294 AC XY: 21847 AN XY: 74334

African (AFR) AF: 0.230 AC: 9559 AN: 41486

American (AMR) AF: 0.315 AC: 4806 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1244 AN: 3470

East Asian (EAS) AF: 0.480 AC: 2486 AN: 5174

South Asian (SAS) AF: 0.416 AC: 2004 AN: 4812

European-Finnish (FIN) AF: 0.295 AC: 3120 AN: 10564

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20080 AN: 67968

Other (OTH) AF: 0.313 AC: 662 AN: 2114

Alfa AF: 0.307 Hom.: 23591

Bravo AF: 0.294

Asia WGS AF: 0.447 AC: 1553 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Leber congenital amaurosis 19 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.3
DANN	Benign	0.52
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4504482; hg19: chr6-99893938; COSMIC: COSV59680780;