Genetic Variant USP6:p.Tyr185Cys (chr17-5135818-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001304284.2(USP6):c.554A>G(p.Tyr185Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000623 in 1,445,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

USP6
NM_001304284.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.35

Variant links:

Genes affected

USP6 (HGNC:12629): (ubiquitin specific peptidase 6) Enables thiol-dependent deubiquitinase. Involved in protein deubiquitination and regulation of vesicle-mediated transport. Located in plasma membrane and recycling endosome. [provided by Alliance of Genome Resources, Apr 2022]

USP6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP6	NM_001304284.2 link	c.554A>G	p.Tyr185Cys	missense_variant	Exon 17 of 38	ENST00000574788.6	NP_001291213.1	P35125-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USP6	ENST00000574788.6 link	c.554A>G	p.Tyr185Cys	missense_variant	Exon 17 of 38	1	NM_001304284.2	ENSP00000460380.1	P35125-1
USP6	ENST00000250066.6 link	c.554A>G	p.Tyr185Cys	missense_variant	Exon 9 of 30	1		ENSP00000250066.6	P35125-1
USP6	ENST00000572949.5 link	n.554A>G		non_coding_transcript_exon_variant	Exon 9 of 29	2		ENSP00000461581.1	P35125-3
USP6	ENST00000575709.5 link	n.554A>G		non_coding_transcript_exon_variant	Exon 9 of 31	2		ENSP00000461817.1	Q15635

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000832

AC:

AN:

240472

Hom.:

AF XY:

0.0000153

AC XY:

AN XY:

130604

show subpopulations

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000623

AC:

AN:

1445758

Hom.:

Cov.:

AF XY:

0.00000973

AC XY:

AN XY:

719614

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.554A>G (p.Y185C) alteration is located in exon 9 (coding exon 8) of the USP6 gene. This alteration results from a A to G substitution at nucleotide position 554, causing the tyrosine (Y) at amino acid position 185 to be replaced by a cysteine (C). 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

Uncertain

0.43

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;T

Eigen

Uncertain

0.21

Eigen_PC

Benign

-0.066

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.80

.;T

M_CAP

Benign

0.0040

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Benign

-0.60

MutationAssessor

Pathogenic

3.9

H;H

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.0

.;D

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.73

MutPred

0.94

Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);

MVP

0.72

MPC

0.91

ClinPred

0.90

GERP RS

0.86

Varity_R

0.36

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over