3-49283991-T-C

Position:

• chr3-49283991-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003363.4(USP4):​c.2536A>G​(p.Ile846Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 1,614,218 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0069 (34 hom.)
• Consequence: USP4 NM_003363.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.85

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0084604025).
• BP6: Variant 3-49283991-T-C is Benign according to our data. Variant chr3-49283991-T-C is described in ClinVar as [Benign]. Clinvar id is 773442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP4	NM_003363.4	c.2536A>G	p.Ile846Val	missense_variant	19/22	ENST00000265560.9	NP_003354.2
USP4	NM_199443.3	c.2395A>G	p.Ile799Val	missense_variant	18/21		NP_955475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP4	ENST00000265560.9	c.2536A>G	p.Ile846Val	missense_variant	19/22	1	NM_003363.4	ENSP00000265560.4
USP4	ENST00000351842.8	c.2395A>G	p.Ile799Val	missense_variant	18/21	1		ENSP00000341028.4
USP4	ENST00000431357.1	c.1750A>G	p.Ile584Val	missense_variant	13/15	5		ENSP00000399079.1
USP4	ENST00000485450.5	n.3050A>G		non_coding_transcript_exon_variant	13/16	2

Frequencies

GnomAD3 genomes AF: 0.00539 AC: 821 AN: 152240 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00830

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00593 AC: 1489 AN: 251272 Hom.: 4 AF XY: 0.00622 AC XY: 845 AN XY: 135780

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00477

Gnomad FIN exome AF: 0.00929

Gnomad NFE exome AF: 0.00837

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00694 AC: 10141 AN: 1461860 Hom.: 34 Cov.: 31 AF XY: 0.00684 AC XY: 4977 AN XY: 727240

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00502

Gnomad4 FIN exome AF: 0.00987

Gnomad4 NFE exome AF: 0.00770

Gnomad4 OTH exome AF: 0.00560

GnomAD4 genome AF: 0.00539 AC: 821 AN: 152358 Hom.: 1 Cov.: 31 AF XY: 0.00513 AC XY: 382 AN XY: 74514

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.00830

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00681 Hom.: 8

Bravo AF: 0.00462

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00633 AC: 768

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00807

EpiControl AF: 0.00765

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.047	.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.095
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0085	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	.;L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.38	N;N
REVEL	Benign	0.067
Sift	Benign	0.28	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0	B;B
Vest4		0.18
MVP		0.30
MPC		0.15
ClinPred		0.0052	T
GERP RS		3.4
Varity_R		0.036
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs41290700; hg19: chr3-49321424;