1-21703628-A-G

Position:

• chr1-21703628-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032236.8(USP48):​c.2516-10T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 835,916 control chromosomes in the GnomAD database, including 8,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (935 hom., cov: 32)
  • Exomes 𝑓: 0.23 (7937 hom.)
• Consequence: USP48 NM_032236.8 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008624
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0740

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-21703628-A-G is Benign according to our data. Variant chr1-21703628-A-G is described in ClinVar as [Benign]. Clinvar id is 769236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP48	NM_032236.8	c.2516-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000308271.14	NP_115612.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP48	ENST00000308271.14	c.2516-10T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_032236.8	ENSP00000309262	P1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 14864 AN: 143810 Hom.: 935 Cov.: 32

Gnomad AFR AF: 0.0536

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0612

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.00242

Gnomad SAS AF: 0.0530

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.0395

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.0844

GnomAD4 exome AF: 0.230 AC: 158840 AN: 692078 Hom.: 7937 Cov.: 18 AF XY: 0.232 AC XY: 78170 AN XY: 336670

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.173

Gnomad4 ASJ exome AF: 0.267

Gnomad4 EAS exome AF: 0.00685

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.384

Gnomad4 NFE exome AF: 0.233

Gnomad4 OTH exome AF: 0.222

GnomAD4 genome AF: 0.103 AC: 14871 AN: 143838 Hom.: 935 Cov.: 32 AF XY: 0.103 AC XY: 7193 AN XY: 69936

Gnomad4 AFR AF: 0.0537

Gnomad4 AMR AF: 0.0611

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.00263

Gnomad4 SAS AF: 0.0532

Gnomad4 FIN AF: 0.208

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.0838

Alfa AF: 0.103 Hom.: 88

Bravo AF: 0.0857

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 24, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.75
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000086
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs55633304; hg19: chr1-22030121;