6-99445822-C-A

Position:

• chr6-99445822-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001346022.3(USP45):​c.1950G>T​(p.Lys650Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00077 in 1,581,962 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (4 hom.)
• Consequence: USP45 NM_001346022.3 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.713

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]

TSTD3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073426664).
• BP6: Variant 6-99445822-C-A is Benign according to our data. Variant chr6-99445822-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3047932.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP45	NM_001346022.3	c.1950G>T	p.Lys650Asn	missense_variant	14/18	ENST00000500704.7	NP_001332951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP45	ENST00000500704.7	c.1950G>T	p.Lys650Asn	missense_variant	14/18	5	NM_001346022.3	ENSP00000424372	P1
USP45	ENST00000327681.10	c.1950G>T	p.Lys650Asn	missense_variant	14/18	1		ENSP00000333376	P1
USP45	ENST00000496518.6	c.*916G>T		3_prime_UTR_variant, NMD_transcript_variant	9/13	1		ENSP00000421248
USP45	ENST00000369233.6	c.1806G>T	p.Lys602Asn	missense_variant	13/17	5		ENSP00000358236

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 264 AN: 152032 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00469

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00598

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00100 AC: 226 AN: 225174 Hom.: 2 AF XY: 0.00103 AC XY: 126 AN XY: 121906

Gnomad AFR exome AF: 0.00461

Gnomad AMR exome AF: 0.000726

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00358

Gnomad SAS exome AF: 0.00221

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.000375

GnomAD4 exome AF: 0.000657 AC: 940 AN: 1429812 Hom.: 4 Cov.: 30 AF XY: 0.000701 AC XY: 497 AN XY: 709300

Gnomad4 AFR exome AF: 0.00583

Gnomad4 AMR exome AF: 0.000676

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00985

Gnomad4 SAS exome AF: 0.00183

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000981

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00183 AC: 278 AN: 152150 Hom.: 2 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74382

Gnomad4 AFR AF: 0.00503

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00580

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000719 Hom.: 1

Bravo AF: 0.00187

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00103 AC: 125

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

USP45-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0029	T;T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.83	.;T;T
MetaRNN	Benign	0.0073	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.080
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.95	P;P;.
Vest4		0.29
MutPred		0.42		Loss of ubiquitination at K650 (P = 0.0116);Loss of ubiquitination at K650 (P = 0.0116);.;
MVP		0.42
MPC		0.24
ClinPred		0.017	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.069
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs112157723; hg19: chr6-99893698;