Genetic Variant USP48:p.Thr739Ala (chr1-21706184-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_032236.8(USP48):c.2215A>G(p.Thr739Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T739L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

USP48
NM_032236.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.63

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

hearing loss, autosomal dominant 85
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

USP48 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-21706183-GT-AA is described in ClinVar as Pathogenic. ClinVar VariationId is 2443813.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032236.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP48	NM_032236.8	MANE Select	c.2215A>G	p.Thr739Ala	missense	Exon 18 of 27	NP_115612.4	Q86UV5-1
USP48	NM_001350167.2		c.2212A>G	p.Thr738Ala	missense	Exon 18 of 27	NP_001337096.1
USP48	NM_001350168.2		c.2212A>G	p.Thr738Ala	missense	Exon 18 of 27	NP_001337097.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP48	ENST00000308271.14	TSL:1 MANE Select	c.2215A>G	p.Thr739Ala	missense	Exon 18 of 27	ENSP00000309262.9	Q86UV5-1
USP48	ENST00000529637.5	TSL:1	c.2251A>G	p.Thr751Ala	missense	Exon 18 of 27	ENSP00000431949.1	Q86UV5-8
USP48	ENST00000400301.5	TSL:1	c.2215A>G	p.Thr739Ala	missense	Exon 18 of 26	ENSP00000383157.1	Q86UV5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

4.6

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.77

REVEL

Benign

0.20

Sift

Benign

0.20

Sift4G

Benign

0.49

Polyphen

0.97

Vest4

0.80

MutPred

0.34

Loss of phosphorylation at T739 (P = 0.0562)

MVP

0.36

MPC

0.57

ClinPred

0.66

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.082

gMVP

0.37

Mutation Taster

=53/47

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over