6-99445822-C-T

Variant names:

• chr6-99445822-C-T
• rs112157723
• NM_001346022.3:c.1950G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001346022.3(USP45):​c.1950G>A​(p.Lys650Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,429,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: USP45 NM_001346022.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.713
• Publications: 0 publications found

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]

PNISR-AS1 (HGNC:40958): (PNISR antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP7: Synonymous conserved (PhyloP=0.713 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346022.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP45	NM_001346022.3	MANE Select	c.1950G>A	p.Lys650Lys	synonymous	Exon 14 of 18	NP_001332951.1	Q70EL2-1
	USP45	NM_001080481.3		c.1950G>A	p.Lys650Lys	synonymous	Exon 14 of 18	NP_001073950.1	Q70EL2-1
	USP45	NM_001346021.3		c.1950G>A	p.Lys650Lys	synonymous	Exon 14 of 18	NP_001332950.1	Q70EL2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP45	ENST00000500704.7	TSL:5 MANE Select	c.1950G>A	p.Lys650Lys	synonymous	Exon 14 of 18	ENSP00000424372.1	Q70EL2-1
	USP45	ENST00000327681.10	TSL:1	c.1950G>A	p.Lys650Lys	synonymous	Exon 14 of 18	ENSP00000333376.6	Q70EL2-1
	USP45	ENST00000496518.6	TSL:1	n.*916G>A		non_coding_transcript_exon	Exon 9 of 13	ENSP00000421248.1	H0Y8J5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1429830 Hom.: 0 Cov.: 30 AF XY: 0.00000282 AC XY: 2 AN XY: 709306

African (AFR) AF: 0.00 AC: 0 AN: 31754

American (AMR) AF: 0.00 AC: 0 AN: 36980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24508

East Asian (EAS) AF: 0.00 AC: 0 AN: 39384

South Asian (SAS) AF: 0.00 AC: 0 AN: 80154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5452

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1100448

Other (OTH) AF: 0.00 AC: 0 AN: 58910

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.6
DANN	Benign	0.52
PhyloP100		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs112157723; hg19: chr6-99893698;