1-21705755-C-A

Position:

• chr1-21705755-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_032236.8(USP48):​c.2356G>T​(p.Ala786Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USP48 NM_032236.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09026727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP48	NM_032236.8	c.2356G>T	p.Ala786Ser	missense_variant	19/27	ENST00000308271.14	NP_115612.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP48	ENST00000308271.14	c.2356G>T	p.Ala786Ser	missense_variant	19/27	1	NM_032236.8	ENSP00000309262.9
USP48	ENST00000529637.5	c.2392G>T	p.Ala798Ser	missense_variant	19/27	1		ENSP00000431949.1
USP48	ENST00000400301.5	c.2356G>T	p.Ala786Ser	missense_variant	19/26	1		ENSP00000383157.1
USP48	ENST00000374732.7	c.970G>T	p.Ala324Ser	missense_variant	8/15	2		ENSP00000363864.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458358 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725360

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 19, 2024

The c.2356G>T (p.A786S) alteration is located in exon 19 (coding exon 19) of the USP48 gene. This alteration results from a G to T substitution at nucleotide position 2356, causing the alanine (A) at amino acid position 786 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	0.083
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Benign	0.85
DEOGEN2	Benign	0.016	.;T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.090	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.14	N;N;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.38	N;N;N;N
REVEL	Benign	0.060
Sift	Benign	0.79	T;T;T;T
Sift4G	Benign	0.71	T;T;T;T
Polyphen		0.11	B;B;.;.
Vest4		0.32
MutPred		0.37		Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);.;.;
MVP		0.043
MPC		0.29
ClinPred		0.41	T
GERP RS		2.7
Varity_R		0.024
gMVP		0.14

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: chr1-22032248;