6-99437248-G-A

Position:

• chr6-99437248-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001346022.3(USP45):​c.2312C>T​(p.Pro771Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP45 NM_001346022.3 missense, splice_region
• Scores: Splicing: ADA: 0.1454
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

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]

USP45 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11933777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP45	NM_001346022.3	c.2312C>T	p.Pro771Leu	missense_variant, splice_region_variant	17/18	ENST00000500704.7	NP_001332951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP45	ENST00000500704.7	c.2312C>T	p.Pro771Leu	missense_variant, splice_region_variant	17/18	5	NM_001346022.3	ENSP00000424372.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2024

The c.2312C>T (p.P771L) alteration is located in exon 17 (coding exon 16) of the USP45 gene. This alteration results from a C to T substitution at nucleotide position 2312, causing the proline (P) at amino acid position 771 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Benign	0.80
DEOGEN2	Benign	0.0029	T;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.79	.;T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.035
Sift	Benign	0.092	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.015	B;B;.
Vest4		0.11
MutPred		0.40		Loss of disorder (P = 0.0328);Loss of disorder (P = 0.0328);.;
MVP		0.39
MPC		0.092
ClinPred		0.098	T
GERP RS		3.7
Varity_R		0.037
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.15
dbscSNV1_RF	Benign	0.42
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-99885124;