18-204585-T-C

Variant names:

• chr18-204585-T-C
• rs1433015862
• NM_005151.4:c.1057T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_005151.4(USP14):​c.1057T>C​(p.Leu353Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: USP14 NM_005151.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.980
• Publications: 0 publications found

Genes affected

USP14 (HGNC:12612): (ubiquitin specific peptidase 14) This gene encodes a member of the ubiquitin-specific processing (UBP) family of proteases that is a deubiquitinating enzyme (DUB) with His and Cys domains. This protein is located in the cytoplasm and cleaves the ubiquitin moiety from ubiquitin-fused precursors and ubiquitinylated proteins. Mice with a mutation that results in reduced expression of the ortholog of this protein are retarded for growth, develop severe tremors by 2 to 3 weeks of age followed by hindlimb paralysis and death by 6 to 10 weeks of age. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

USP14 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 18-204585-T-C is Benign according to our data. Variant chr18-204585-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 742955.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.98 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005151.4. 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
	USP14	NM_005151.4	MANE Select	c.1057T>C	p.Leu353Leu	synonymous	Exon 13 of 16	NP_005142.1	P54578-1
	USP14	NM_001037334.2		c.952T>C	p.Leu318Leu	synonymous	Exon 12 of 15	NP_001032411.1	P54578-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP14	ENST00000261601.8	TSL:1 MANE Select	c.1057T>C	p.Leu353Leu	synonymous	Exon 13 of 16	ENSP00000261601.6	P54578-1
	USP14	ENST00000947712.1		c.1066T>C	p.Leu356Leu	synonymous	Exon 13 of 16	ENSP00000617771.1
	USP14	ENST00000873770.1		c.1048T>C	p.Leu350Leu	synonymous	Exon 13 of 16	ENSP00000543829.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000418 AC: 1 AN: 239166 AF XY: 0.00000774

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448994 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720376

African (AFR) AF: 0.00 AC: 0 AN: 32812

American (AMR) AF: 0.00 AC: 0 AN: 41222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25796

East Asian (EAS) AF: 0.00 AC: 0 AN: 39334

South Asian (SAS) AF: 0.00 AC: 0 AN: 82976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5426

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108222

Other (OTH) AF: 0.00 AC: 0 AN: 59948

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely 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	-0.50
CADD	Benign	10
DANN	Benign	0.78
PhyloP100		0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs1433015862; hg19: chr18-204585;