1-21706183-GT-AA

Variant names:

• chr1-21706183-GT-AA
• NM_032236.8:c.2215_2216delACinsTT

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_032236.8(USP48):​c.2215_2216delACinsTT​(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T739M) has been classified as Uncertain significance.

• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
USP48	NM_032236.8	c.2215_2216delACinsTT	p.Thr739Leu	missense_variant		ENST00000308271.14	NP_115612.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP48	ENST00000308271.14	c.2215_2216delACinsTT	p.Thr739Leu	missense_variant		1	NM_032236.8	ENSP00000309262.9
USP48	ENST00000529637.5	c.2251_2252delACinsTT	p.Thr751Leu	missense_variant		1		ENSP00000431949.1
USP48	ENST00000400301.5	c.2215_2216delACinsTT	p.Thr739Leu	missense_variant		1		ENSP00000383157.1
USP48	ENST00000374732.7	c.829_830delACinsTT	p.Thr277Leu	missense_variant		2		ENSP00000363864.3

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

Jan 27, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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;