rs372804375

Variant names:

• chr3-49111025-C-A
• rs372804375
• NM_001199161.2:c.3470G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-49111025-C-A
• chr3-49111025-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001199161.2(USP19):​c.3470G>T​(p.Arg1157Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1157Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USP19 NM_001199161.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.47
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP19	NM_001199161.2	c.3470G>T	p.Arg1157Leu	missense_variant	Exon 23 of 27	ENST00000417901.6	NP_001186090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP19	ENST00000417901.6	c.3470G>T	p.Arg1157Leu	missense_variant	Exon 23 of 27	1	NM_001199161.2	ENSP00000395260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461704 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0061	.;.;.;T;T;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;D;.;D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.6	.;.;.;.;M;.
PhyloP100		7.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;D;D;.
Vest4		0.71
MutPred		0.57		Loss of solvent accessibility (P = 0.0442);.;.;Loss of solvent accessibility (P = 0.0442);.;.;
MVP		0.31
MPC		1.6
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.58
Mutation Taster		=26/74	disease causing

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: rs372804375; hg19: chr3-49148458;