3-179653236-G-A

Position:

• chr3-179653236-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003940.3(USP13):​c.11G>A​(p.Arg4Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000677 in 1,547,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (0 hom.)
• Consequence: USP13 NM_003940.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

Genes affected

USP13 (HGNC:12611): (ubiquitin specific peptidase 13) Enables several functions, including BAT3 complex binding activity; chaperone binding activity; and cysteine-type peptidase activity. Involved in several processes, including maintenance of unfolded protein involved in ERAD pathway; regulation of cellular catabolic process; and regulation of transcription, DNA-templated. Acts upstream of or within protein deubiquitination and protein stabilization. Predicted to be located in nucleoplasm. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000288698 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057159692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP13	NM_003940.3	c.11G>A	p.Arg4Gln	missense_variant	1/21	ENST00000263966.8	NP_003931.2
USP13	XM_011513269.2	c.11G>A	p.Arg4Gln	missense_variant	1/20		XP_011511571.1
USP13	XM_017007426.2	c.11G>A	p.Arg4Gln	missense_variant	1/20		XP_016862915.1
USP13	XM_047449154.1	c.11G>A	p.Arg4Gln	missense_variant	1/19		XP_047305110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP13	ENST00000263966.8	c.11G>A	p.Arg4Gln	missense_variant	1/21	1	NM_003940.3	ENSP00000263966.3
ENSG00000288698	ENST00000680408.1	n.*383+12380G>A		intron_variant				ENSP00000506198.1

Frequencies

GnomAD3 genomes AF: 0.000397 AC: 60 AN: 151272 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000592

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000193

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000592

Gnomad OTH AF: 0.000964

GnomAD3 exomes AF: 0.000501 AC: 74 AN: 147626 Hom.: 0 AF XY: 0.000454 AC XY: 36 AN XY: 79222

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.000814

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000428

Gnomad NFE exome AF: 0.000810

Gnomad OTH exome AF: 0.000469

GnomAD4 exome AF: 0.000708 AC: 988 AN: 1395884 Hom.: 0 Cov.: 30 AF XY: 0.000692 AC XY: 477 AN XY: 688866

Gnomad4 AFR exome AF: 0.0000637

Gnomad4 AMR exome AF: 0.000841

Gnomad4 ASJ exome AF: 0.0000799

Gnomad4 EAS exome AF: 0.0000281

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.000213

Gnomad4 NFE exome AF: 0.000834

Gnomad4 OTH exome AF: 0.000674

GnomAD4 genome AF: 0.000396 AC: 60 AN: 151384 Hom.: 0 Cov.: 32 AF XY: 0.000325 AC XY: 24 AN XY: 73956

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000592

Gnomad4 ASJ AF: 0.000290

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000193

Gnomad4 NFE AF: 0.000592

Gnomad4 OTH AF: 0.000954

Alfa AF: 0.000516 Hom.: 0

Bravo AF: 0.000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000375 AC: 3

ExAC AF: 0.000323 AC: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.11G>A (p.R4Q) alteration is located in exon 1 (coding exon 1) of the USP13 gene. This alteration results from a G to A substitution at nucleotide position 11, causing the arginine (R) at amino acid position 4 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.080
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.062
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.53	P
Vest4		0.38
MVP		0.38
MPC		0.47
ClinPred		0.12	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs374896625; hg19: chr3-179371024;