6-99445839-T-A

Variant names:

• chr6-99445839-T-A
• NM_001346022.3:c.1933A>T

Variant summary

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

The NM_001346022.3(USP45):​c.1933A>T​(p.Thr645Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,604 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: USP45 NM_001346022.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP45	NM_001346022.3	c.1933A>T	p.Thr645Ser	missense_variant	Exon 14 of 18	ENST00000500704.7	NP_001332951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP45	ENST00000500704.7	c.1933A>T	p.Thr645Ser	missense_variant	Exon 14 of 18	5	NM_001346022.3	ENSP00000424372.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442604 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 716652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1933A>T (p.T645S) alteration is located in exon 14 (coding exon 13) of the USP45 gene. This alteration results from a A to T substitution at nucleotide position 1933, causing the threonine (T) at amino acid position 645 to be replaced by a serine (S). 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	0.15
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0064	T;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Uncertain	0.36
Sift	Benign	0.085	T;T;D
Sift4G	Benign	0.12	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.54
MutPred		0.47		Gain of disorder (P = 0.0836);Gain of disorder (P = 0.0836);.;
MVP		0.57
MPC		0.43
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.39
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
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: chr6-99893715;