chr1-21706794-G-A

Position:

• chr1-21706794-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_032236.8(USP48):​c.2038C>T​(p.Pro680Ser) 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.

• Frequency: Genomes: not found (cov: 31)
• Consequence: USP48 NM_032236.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP48	NM_032236.8	c.2038C>T	p.Pro680Ser	missense_variant	16/27	ENST00000308271.14	NP_115612.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP48	ENST00000308271.14	c.2038C>T	p.Pro680Ser	missense_variant	16/27	1	NM_032236.8	ENSP00000309262.9
USP48	ENST00000529637.5	c.2074C>T	p.Pro692Ser	missense_variant	16/27	1		ENSP00000431949.1
USP48	ENST00000400301.5	c.2038C>T	p.Pro680Ser	missense_variant	16/26	1		ENSP00000383157.1
USP48	ENST00000374732.7	c.652C>T	p.Pro218Ser	missense_variant	5/15	2		ENSP00000363864.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

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

Dec 02, 2024

The c.2038C>T (p.P680S) alteration is located in exon 16 (coding exon 16) of the USP48 gene. This alteration results from a C to T substitution at nucleotide position 2038, causing the proline (P) at amino acid position 680 to be replaced by a serine (S). 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	0.18
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;T;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.8	M;M;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.51
MutPred		0.33		Gain of MoRF binding (P = 0.0565);Gain of MoRF binding (P = 0.0565);.;.;
MVP		0.57
MPC		0.87
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.83
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-22033287;