1-62445195-A-G

Position:

• chr1-62445195-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003368.5(USP1):​c.1015A>G​(p.Ile339Val) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP1 NM_003368.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.196

Genes affected

USP1 (HGNC:12607): (ubiquitin specific peptidase 1) This gene encodes a member of the ubiquitin-specific processing (UBP) family of proteases that is a deubiquitinating enzyme (DUB) with His and Cys domains. This protein is located in the cytoplasm and cleaves the ubiquitin moiety from ubiquitin-fused precursors and ubiquitinylated proteins. The protein specifically deubiquitinates a protein in the Fanconi anemia (FA) DNA repair pathway. Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050218552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP1	NM_003368.5	c.1015A>G	p.Ile339Val	missense_variant	6/9	ENST00000339950.5	NP_003359.3
USP1	NM_001017415.2	c.1015A>G	p.Ile339Val	missense_variant	6/9		NP_001017415.1
USP1	NM_001017416.2	c.1015A>G	p.Ile339Val	missense_variant	6/9		NP_001017416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP1	ENST00000339950.5	c.1015A>G	p.Ile339Val	missense_variant	6/9	1	NM_003368.5	ENSP00000343526.4
USP1	ENST00000371146.5	c.1015A>G	p.Ile339Val	missense_variant	6/9	5		ENSP00000360188.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Mar 01, 2023

The c.1015A>G (p.I339V) alteration is located in exon 6 (coding exon 5) of the USP1 gene. This alteration results from a A to G substitution at nucleotide position 1015, causing the isoleucine (I) at amino acid position 339 to be replaced by a valine (V). 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	0.092
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.77	T;.
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.056
Sift	Benign	0.16	T;T
Sift4G	Benign	0.092	T;T
Polyphen		0.0010	B;B
Vest4		0.074
MutPred		0.38		Gain of loop (P = 0.069);Gain of loop (P = 0.069);
MVP		0.19
MPC		0.082
ClinPred		0.063	T
GERP RS		-2.5
Varity_R		0.018
gMVP		0.15

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: chr1-62910866;