3-49286229-C-T

Position:

• chr3-49286229-C-T

Variant summary

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

The NM_003363.4(USP4):​c.2069G>A​(p.Ser690Asn) 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: USP4 NM_003363.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0940

Genes affected

USP4 (HGNC:12627): (ubiquitin specific peptidase 4) The protein encoded by this gene is a protease that deubiquitinates target proteins such as ADORA2A and TRIM21. The encoded protein shuttles between the nucleus and cytoplasm and is involved in maintaining operational fidelity in the endoplasmic reticulum. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

USP4 (HGNC:):

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=0.05734399).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP4	NM_003363.4	c.2069G>A	p.Ser690Asn	missense_variant	16/22	ENST00000265560.9	NP_003354.2
USP4	NM_199443.3	c.1928G>A	p.Ser643Asn	missense_variant	15/21		NP_955475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP4	ENST00000265560.9	c.2069G>A	p.Ser690Asn	missense_variant	16/22	1	NM_003363.4	ENSP00000265560.4

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

Jan 02, 2024

The c.2069G>A (p.S690N) alteration is located in exon 16 (coding exon 16) of the USP4 gene. This alteration results from a G to A substitution at nucleotide position 2069, causing the serine (S) at amino acid position 690 to be replaced by an asparagine (N). 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	0.078
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.1
DANN	Benign	0.40
DEOGEN2	Benign	0.034	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.057	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	.;L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.12	N;N
REVEL	Benign	0.021
Sift	Benign	0.32	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0090	B;B
Vest4		0.14
MutPred		0.33		.;Gain of glycosylation at S690 (P = 0.0262);
MVP		0.20
MPC		0.16
ClinPred		0.065	T
GERP RS		-0.17
Varity_R		0.023
gMVP		0.11

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: chr3-49323662;