chr1-21706177-A-G

Position:

• chr1-21706177-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BS2_Supporting

The NM_032236.8(USP48):​c.2222T>C​(p.Val741Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: USP48 NM_032236.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.742

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 Likely_benign. Variant got -2 ACMG points.

• 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=0.098332554).
• BS2: High AC in GnomAdExome4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP48	NM_032236.8	c.2222T>C	p.Val741Ala	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.2222T>C	p.Val741Ala	missense_variant	18/27	1	NM_032236.8	ENSP00000309262	P1
USP48	ENST00000529637.5	c.2258T>C	p.Val753Ala	missense_variant	18/27	1		ENSP00000431949
USP48	ENST00000400301.5	c.2222T>C	p.Val741Ala	missense_variant	18/26	1		ENSP00000383157
USP48	ENST00000374732.7	c.836T>C	p.Val279Ala	missense_variant	7/15	2		ENSP00000363864

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 250110 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135238

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000198

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461328 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 726930

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: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

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

Mar 29, 2022

The c.2222T>C (p.V741A) alteration is located in exon 18 (coding exon 18) of the USP48 gene. This alteration results from a T to C substitution at nucleotide position 2222, causing the valine (V) at amino acid position 741 to be replaced by an alanine (A). 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	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.017	.;T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.098	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.12	N;N;N;N
REVEL	Benign	0.082
Sift	Benign	0.43	T;T;T;T
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.0010	B;B;.;.
Vest4		0.30
MutPred		0.41		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;.;
MVP		0.082
MPC		0.39
ClinPred		0.054	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.018
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs539331775; hg19: chr1-22032670;