1-21721716-C-A

Variant names:

• chr1-21721716-C-A
• rs757075449
• NM_032236.8:c.1697G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032236.8(USP48):​c.1697G>T​(p.Arg566Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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. R566H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP48 NM_032236.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.24
• Publications: 1 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP48	NM_032236.8	MANE Select	c.1697G>T	p.Arg566Leu	missense	Exon 13 of 27	NP_115612.4	Q86UV5-1
	USP48	NM_001350167.2		c.1694G>T	p.Arg565Leu	missense	Exon 13 of 27	NP_001337096.1
	USP48	NM_001350168.2		c.1697G>T	p.Arg566Leu	missense	Exon 13 of 27	NP_001337097.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP48	ENST00000308271.14	TSL:1 MANE Select	c.1697G>T	p.Arg566Leu	missense	Exon 13 of 27	ENSP00000309262.9	Q86UV5-1
	USP48	ENST00000529637.5	TSL:1	c.1694G>T	p.Arg565Leu	missense	Exon 13 of 27	ENSP00000431949.1	Q86UV5-8
	USP48	ENST00000400301.5	TSL:1	c.1697G>T	p.Arg566Leu	missense	Exon 13 of 26	ENSP00000383157.1	Q86UV5-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.95	P
Vest4		0.78
MutPred		0.49		Loss of helix (P = 0.0033)
MVP		0.61
MPC		1.7
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.94
Mutation Taster		=27/73	disease causing

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: rs757075449; hg19: chr1-22048209;