rs780495921

Variant names:

• chr3-49110273-G-A
• rs780495921
• NM_001199161.2:c.3949C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001199161.2(USP19):​c.3949C>T​(p.Arg1317Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000996 in 1,606,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: USP19 NM_001199161.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199161.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP19	NM_001199161.2	MANE Select	c.3949C>T	p.Arg1317Trp	missense	Exon 26 of 27	NP_001186090.1	O94966-6
	USP19	NM_001389594.1		c.3949C>T	p.Arg1317Trp	missense	Exon 26 of 27	NP_001376523.1	A0A8I5KXK1
	USP19	NM_001389595.1		c.3949C>T	p.Arg1317Trp	missense	Exon 26 of 27	NP_001376524.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP19	ENST00000417901.6	TSL:1 MANE Select	c.3949C>T	p.Arg1317Trp	missense	Exon 26 of 27	ENSP00000395260.1	O94966-6
	USP19	ENST00000398888.6	TSL:1	c.3640C>T	p.Arg1214Trp	missense	Exon 25 of 26	ENSP00000381863.2	O94966-1
	USP19	ENST00000398896.6	TSL:1	c.3601C>T	p.Arg1201Trp	missense	Exon 25 of 26	ENSP00000381870.3	O94966-4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000655 AC: 16 AN: 244276 AF XY: 0.0000529

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000781

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.00000963 AC: 14 AN: 1453800 Hom.: 0 Cov.: 31 AF XY: 0.00000831 AC XY: 6 AN XY: 722190

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.0000226 AC: 1 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25732

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39522

South Asian (SAS) AF: 0.0000469 AC: 4 AN: 85314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106774

Other (OTH) AF: 0.00 AC: 0 AN: 60018

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000496 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.45		Loss of disorder (P = 0.004)
MVP		0.73
MPC		1.5
ClinPred		0.50	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.80
Mutation Taster		=12/88	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: rs780495921; hg19: chr3-49147706;