Variant 1-21706177-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS2_Supporting

The NM_032236.8(USP48):c.2222T>C(p.Val741Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

USP48
NM_032236.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.742

Variant links:

Genes affected

USP48 (HGNC:18533): (ubiquitin specific peptidase 48) This gene encodes a protein containing domains that associate it with the peptidase family C19, also known as family 2 of ubiquitin carboxyl-terminal hydrolases. Family members function as deubiquitinating enzymes, recognizing and hydrolyzing the peptide bond at the C-terminal glycine of ubiquitin. Enzymes in peptidase family C19 are involved in the processing of poly-ubiquitin precursors as well as that of ubiquitinated proteins. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

USP48 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), USP48. . Gene score misZ 4.3729 (greater than the threshold 3.09). Trascript score misZ 4.4487 (greater than threshold 3.09). GenCC has associacion of gene with schizophrenia, hearing loss, autosomal dominant 85.

BP4

Computational evidence support a benign effect (MetaRNN=0.098332554).

BS2

High AC in GnomAdExome4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP48	NM_032236.8 linkuse as main transcript	c.2222T>C	p.Val741Ala	missense_variant	18/27	ENST00000308271.14	NP_115612.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP48	ENST00000308271.14 linkuse as main transcript	c.2222T>C	p.Val741Ala	missense_variant	18/27	1	NM_032236.8	ENSP00000309262	P1	Q86UV5-1
USP48	ENST00000529637.5 linkuse as main transcript	c.2258T>C	p.Val753Ala	missense_variant	18/27	1		ENSP00000431949		Q86UV5-8
USP48	ENST00000400301.5 linkuse as main transcript	c.2222T>C	p.Val741Ala	missense_variant	18/26	1		ENSP00000383157		Q86UV5-2
USP48	ENST00000374732.7 linkuse as main transcript	c.836T>C	p.Val279Ala	missense_variant	7/15	2		ENSP00000363864

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

250110

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135238

show subpopulations

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 SAS exome

AF:

0.000198

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461328

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726930

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The c.2222T>C (p.V741A) alteration is located in exon 18 (coding exon 18) of the USP48 gene. This alteration results from a T to C substitution at nucleotide position 2222, causing the valine (V) at amino acid position 741 to be replaced by an alanine (A). 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

0.14

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.017

.;T;.;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.76

T;T;T;T

M_CAP

Benign

0.0079

MetaRNN

Benign

0.098

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.81

L;L;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.12

N;N;N;N

REVEL

Benign

0.082

Sift

Benign

0.43

T;T;T;T

Sift4G

Benign

0.44

T;T;T;T

Polyphen

0.0010

B;B;.;.

Vest4

0.30

MutPred

0.41

Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;.;

MVP

0.082

MPC

0.39

ClinPred

0.054

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.018

gMVP

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over