1-21715390-A-G

Variant names:

• chr1-21715390-A-G
• rs77218913
• NM_032236.8:c.1962T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_032236.8(USP48):​c.1962T>C​(p.His654His) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,589,658 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (16 hom.)
• Consequence: USP48 NM_032236.8 splice_region, synonymous
• Scores: Splicing: ADA: 0.03784
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.60
• Publications: 2 publications found

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]

USP48 Gene-Disease associations (from GenCC):

• hearing loss, autosomal dominant 85

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 1-21715390-A-G is Benign according to our data. Variant chr1-21715390-A-G is described in ClinVar as Benign. ClinVar VariationId is 2672327.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.6 with no splicing effect.
• BS2: High AC in GnomAd4 at 700 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032236.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP48	NM_032236.8	MANE Select	c.1962T>C	p.His654His	splice_region synonymous	Exon 15 of 27	NP_115612.4	Q86UV5-1
	USP48	NM_001350167.2		c.1959T>C	p.His653His	splice_region synonymous	Exon 15 of 27	NP_001337096.1
	USP48	NM_001350168.2		c.1959T>C	p.His653His	splice_region synonymous	Exon 15 of 27	NP_001337097.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP48	ENST00000308271.14	TSL:1 MANE Select	c.1962T>C	p.His654His	splice_region synonymous	Exon 15 of 27	ENSP00000309262.9	Q86UV5-1
	USP48	ENST00000529637.5	TSL:1	c.1959T>C	p.His653His	splice_region synonymous	Exon 15 of 27	ENSP00000431949.1	Q86UV5-8
	USP48	ENST00000400301.5	TSL:1	c.1962T>C	p.His654His	splice_region synonymous	Exon 15 of 26	ENSP00000383157.1	Q86UV5-2

Frequencies

GnomAD3 genomes AF: 0.00459 AC: 699 AN: 152244 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00214 AC: 529 AN: 247582 AF XY: 0.00192

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000275

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.000941 AC: 1352 AN: 1437296 Hom.: 16 Cov.: 26 AF XY: 0.000921 AC XY: 660 AN XY: 716252

African (AFR) AF: 0.0155 AC: 507 AN: 32798

American (AMR) AF: 0.00180 AC: 78 AN: 43288

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 429 AN: 25746

East Asian (EAS) AF: 0.00 AC: 0 AN: 39412

South Asian (SAS) AF: 0.0000823 AC: 7 AN: 85104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5646

European-Non Finnish (NFE) AF: 0.000160 AC: 175 AN: 1092602

Other (OTH) AF: 0.00252 AC: 150 AN: 59418

GnomAD4 genome AF: 0.00459 AC: 700 AN: 152362 Hom.: 5 Cov.: 33 AF XY: 0.00447 AC XY: 333 AN XY: 74512

African (AFR) AF: 0.0143 AC: 593 AN: 41588

American (AMR) AF: 0.00255 AC: 39 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68036

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00247 Hom.: 4

Bravo AF: 0.00535

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.000656

EpiControl AF: 0.000297

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	11
DANN	Benign	0.83
PhyloP100		1.6
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.038
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs77218913; hg19: chr1-22041883; COSMIC: COSV99058176;