1-21706183-GT-AA

Position:

• chr1-21706183-GT-AA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_032236.8(USP48):​c.2215_2216delinsTT​(p.Thr739Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP48 NM_032236.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.07

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 4 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.
• PP5: Variant 1-21706183-GT-AA is Pathogenic according to our data. Variant chr1-21706183-GT-AA is described in ClinVar as [Pathogenic]. Clinvar id is 2443813.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP48	NM_032236.8	c.2215_2216delinsTT	p.Thr739Leu	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	c.2215_2216delinsTT	p.Thr739Leu	missense_variant	18/27	1	NM_032236.8	ENSP00000309262	P1
USP48	ENST00000400301.5	c.2215_2216delinsTT	p.Thr739Leu	missense_variant	18/26	1		ENSP00000383157
USP48	ENST00000529637.5	c.2251_2252delinsTT	p.Thr751Leu	missense_variant	18/27	1		ENSP00000431949
USP48	ENST00000374732.7	c.829_830delinsTT	p.Thr277Leu	missense_variant	7/15	2		ENSP00000363864

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hearing loss, autosomal dominant 85 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr1-22032676;