rs148077433

Variant names:

• chr6-99443599-G-A
• rs148077433
• NM_001346022.3:c.2039C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001346022.3(USP45):​c.2039C>T​(p.Ala680Val) variant causes a missense change. The variant allele was found at a frequency of 0.000638 in 1,609,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: USP45 NM_001346022.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.54
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05749154).

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.2039C>T	p.Ala680Val	missense	Exon 15 of 18	NP_001332951.1	Q70EL2-1
	USP45	NM_001080481.3		c.2039C>T	p.Ala680Val	missense	Exon 15 of 18	NP_001073950.1	Q70EL2-1
	USP45	NM_001346021.3		c.2039C>T	p.Ala680Val	missense	Exon 15 of 18	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.2039C>T	p.Ala680Val	missense	Exon 15 of 18	ENSP00000424372.1	Q70EL2-1
	USP45	ENST00000327681.10	TSL:1	c.2039C>T	p.Ala680Val	missense	Exon 15 of 18	ENSP00000333376.6	Q70EL2-1
	USP45	ENST00000496518.6	TSL:1	n.*1005C>T		non_coding_transcript_exon	Exon 10 of 13	ENSP00000421248.1	H0Y8J5

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000647

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000463 AC: 116 AN: 250620 AF XY: 0.000465

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000961

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000670 AC: 976 AN: 1457064 Hom.: 0 Cov.: 30 AF XY: 0.000633 AC XY: 459 AN XY: 724728

African (AFR) AF: 0.000120 AC: 4 AN: 33438

American (AMR) AF: 0.000112 AC: 5 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.00 AC: 0 AN: 85144

European-Finnish (FIN) AF: 0.000207 AC: 11 AN: 53194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.000839 AC: 931 AN: 1109262

Other (OTH) AF: 0.000416 AC: 25 AN: 60154

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74430

African (AFR) AF: 0.000120 AC: 5 AN: 41556

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000644 Hom.: 2

Bravo AF: 0.000355

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000593 AC: 72

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.050
Sift	Benign	0.29	T
Sift4G	Benign	0.13	T
Polyphen		0.010	B
Vest4		0.19
MVP		0.42
MPC		0.093
ClinPred		0.074	T
GERP RS		4.1
Varity_R		0.077
gMVP		0.43
Mutation Taster		=95/5	polymorphism

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: rs148077433; hg19: chr6-99891475; COSMIC: COSV59680903; COSMIC: COSV59680903;