6-99439831-T-G

Position:

• chr6-99439831-T-G

Variant summary

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

The NM_001346022.3(USP45):​c.2098A>C​(p.Asn700His) variant causes a missense change involving the alteration of a 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: 33)
• Consequence: USP45 NM_001346022.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

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]

TSTD3 (HGNC:):

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, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP45	NM_001346022.3	c.2098A>C	p.Asn700His	missense_variant	16/18	ENST00000500704.7	NP_001332951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP45	ENST00000500704.7	c.2098A>C	p.Asn700His	missense_variant	16/18	5	NM_001346022.3	ENSP00000424372	P1
USP45	ENST00000327681.10	c.2098A>C	p.Asn700His	missense_variant	16/18	1		ENSP00000333376	P1
USP45	ENST00000496518.6	c.*1064A>C		3_prime_UTR_variant, NMD_transcript_variant	11/13	1		ENSP00000421248
USP45	ENST00000369233.6	c.1954A>C	p.Asn652His	missense_variant	15/17	5		ENSP00000358236

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Genetic Services Laboratory, University of Chicago

Nov 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	0.0060	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0043	T;T;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.93
MutPred		0.70		Gain of disorder (P = 0.0667);Gain of disorder (P = 0.0667);.;
MVP		0.80
MPC		0.49
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.82
gMVP		0.56

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: chr6-99887707;