chr3-49109127-C-T

Variant names:

• chr3-49109127-C-T
• rs1228948401
• ENST00000398888.6:c.3788G>A

Variant summary

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

The NM_001389594.1(USP19):​c.4097G>A​(p.Gly1366Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,544,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: USP19 NM_001389594.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07511899).
• BS2: High AC in GnomAdExome4 at 36 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001389594.1. 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.4039-599G>A		intron	N/A	NP_001186090.1	O94966-6
	USP19	NM_001389594.1		c.4097G>A	p.Gly1366Glu	missense	Exon 27 of 27	NP_001376523.1	A0A8I5KXK1
	USP19	NM_001389595.1		c.4097G>A	p.Gly1366Glu	missense	Exon 27 of 27	NP_001376524.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP19	ENST00000398888.6	TSL:1	c.3788G>A	p.Gly1263Glu	missense	Exon 26 of 26	ENSP00000381863.2	O94966-1
	USP19	ENST00000417901.6	TSL:1 MANE Select	c.4039-599G>A		intron	N/A	ENSP00000395260.1	O94966-6
	USP19	ENST00000398896.6	TSL:1	c.3691-599G>A		intron	N/A	ENSP00000381870.3	O94966-4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152048 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 149662 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: 0.0000259 AC: 36 AN: 1392566 Hom.: 0 Cov.: 30 AF XY: 0.0000218 AC XY: 15 AN XY: 688328

African (AFR) AF: 0.00 AC: 0 AN: 30664

American (AMR) AF: 0.00 AC: 0 AN: 30562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23848

East Asian (EAS) AF: 0.00 AC: 0 AN: 36718

South Asian (SAS) AF: 0.00 AC: 0 AN: 78474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5552

European-Non Finnish (NFE) AF: 0.0000324 AC: 35 AN: 1080228

Other (OTH) AF: 0.0000174 AC: 1 AN: 57422

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74244

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Benign	0.079
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.071
Sift	Benign	0.032	D
Sift4G	Uncertain	0.021	D
Polyphen		0.0	B
Vest4		0.12
MutPred		0.22		Gain of solvent accessibility (P = 0.0638)
MVP		0.043
MPC		0.72
ClinPred		0.25	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.10
gMVP		0.26
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1228948401; hg19: chr3-49146560; COSMIC: COSV99065393; COSMIC: COSV99065393;