6-99435734-G-T

Variant names:

• chr6-99435734-G-T
• NM_001346022.3:c.2427C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001346022.3(USP45):​c.2427C>A​(p.Phe809Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP45 NM_001346022.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP45	NM_001346022.3	c.2427C>A	p.Phe809Leu	missense_variant	Exon 18 of 18	ENST00000500704.7	NP_001332951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP45	ENST00000500704.7	c.2427C>A	p.Phe809Leu	missense_variant	Exon 18 of 18	5	NM_001346022.3	ENSP00000424372.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2427C>A (p.F809L) alteration is located in exon 18 (coding exon 17) of the USP45 gene. This alteration results from a C to A substitution at nucleotide position 2427, causing the phenylalanine (F) at amino acid position 809 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T;T;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.3	M;M;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.71
MutPred		0.79		Gain of disorder (P = 0.0691);Gain of disorder (P = 0.0691);.;
MVP		0.43
MPC		0.52
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.89
gMVP		0.70

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-99883610;