rs796052187

Positions:

• chr3-49116600-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4 BP6

The NM_001199161.2(USP19):​c.1134G>T​(p.Glu378Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USP19 NM_001199161.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.99

Genes affected

USP19 (HGNC:12617): (ubiquitin specific peptidase 19) Protein ubiquitination controls many intracellular processes, including cell cycle progression, transcriptional activation, and signal transduction. This dynamic process, involving ubiquitin conjugating enzymes and deubiquitinating enzymes, adds and removes ubiquitin. Deubiquitinating enzymes are cysteine proteases that specifically cleave ubiquitin from ubiquitin-conjugated protein substrates. This protein is a ubiquitin protein ligase and plays a role in muscle wasting. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, USP19
• BP4: Computational evidence support a benign effect (MetaRNN=0.35449827).
• BP6: Variant 3-49116600-C-A is Benign according to our data. Variant chr3-49116600-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 207923.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP19	NM_001199161.2	c.1134G>T	p.Glu378Asp	missense_variant	8/27	ENST00000417901.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP19	ENST00000417901.6	c.1134G>T	p.Glu378Asp	missense_variant	8/27	1	NM_001199161.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Long QT syndrome Benign:1

Likely benign, no assertion criteria provided

research

Medical Research Institute, Tokyo Medical and Dental University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	0.19
Eigen_PC	Benign	0.091
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.35	T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.99	D;D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Uncertain	0.045	D;D;D;D;D;D;.
Polyphen		0.83, 0.94	.;.;.;P;P;.;.
Vest4		0.47
MutPred		0.53		Loss of helix (P = 0.0558);.;.;Loss of helix (P = 0.0558);.;.;.;
MVP		0.55
MPC		0.39
ClinPred		0.84	D
GERP RS		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs796052187; hg19: chr3-49154033;