3-49108968-C-A

Variant names:

• chr3-49108968-C-A
• rs201834559
• ENST00000398888.6:c.3947G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000398888.6(USP19):​c.3947G>T​(p.Arg1316Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,457,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1316H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: USP19 ENST00000398888.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.169
• Publications: 4 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.094420016).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP19	NM_001199161.2	c.4039-440G>T		intron_variant	Intron 26 of 26	ENST00000417901.6	NP_001186090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP19	ENST00000417901.6	c.4039-440G>T		intron_variant	Intron 26 of 26	1	NM_001199161.2	ENSP00000395260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 243982 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1457160 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724670

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 85712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109670

Other (OTH) AF: 0.00 AC: 0 AN: 60162

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.81	.;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.094	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;N;.
PhyloP100		0.17
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.28	N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.010	D;D;D
Sift4G	Benign	0.070	T;T;T
Polyphen		0.039	B;B;.
Vest4		0.23
MutPred		0.28		Loss of MoRF binding (P = 0.0266);.;.;
MVP		0.21
MPC		0.82
ClinPred		0.28	T
GERP RS		1.0
Varity_R		0.080
gMVP		0.32
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs201834559; hg19: chr3-49146401;