6-99435837-G-A

Variant names:

• chr6-99435837-G-A
• rs375582786
• NM_001346022.3:c.2324C>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.2324C>T​(p.Ala775Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000703 in 1,607,470 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 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: USP45 NM_001346022.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.68
• 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=0.050549835).

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.2324C>T	p.Ala775Val	missense	Exon 18 of 18	NP_001332951.1	Q70EL2-1
	USP45	NM_001080481.3		c.2324C>T	p.Ala775Val	missense	Exon 18 of 18	NP_001073950.1	Q70EL2-1
	USP45	NM_001346021.3		c.2324C>T	p.Ala775Val	missense	Exon 18 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.2324C>T	p.Ala775Val	missense	Exon 18 of 18	ENSP00000424372.1	Q70EL2-1
	USP45	ENST00000327681.10	TSL:1	c.2324C>T	p.Ala775Val	missense	Exon 18 of 18	ENSP00000333376.6	Q70EL2-1
	USP45	ENST00000496518.6	TSL:1	n.*1290C>T		non_coding_transcript_exon	Exon 13 of 13	ENSP00000421248.1	H0Y8J5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000411 AC: 10 AN: 243456 AF XY: 0.0000456

Gnomad AFR exome AF: 0.000124

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: 0.0000360

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000742 AC: 108 AN: 1455338 Hom.: 0 Cov.: 32 AF XY: 0.0000746 AC XY: 54 AN XY: 723816

African (AFR) AF: 0.0000603 AC: 2 AN: 33144

American (AMR) AF: 0.00 AC: 0 AN: 43162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25830

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39532

South Asian (SAS) AF: 0.000284 AC: 24 AN: 84546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.0000649 AC: 72 AN: 1109928

Other (OTH) AF: 0.0000665 AC: 4 AN: 60156

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152132 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74304

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

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

Alfa AF: 0.0000966 Hom.: 0

Bravo AF: 0.0000416

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.073
Sift	Uncertain	0.024	D
Sift4G	Benign	0.18	T
Polyphen		0.28	B
Vest4		0.048
MVP		0.25
MPC		0.10
ClinPred		0.072	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.18
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs375582786; hg19: chr6-99883713; COSMIC: COSV59680658; COSMIC: COSV59680658;