17-5133942-A-C

Variant names:

• chr17-5133942-A-C
• rs2073166493
• NM_001304284.2:c.440A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001304284.2(USP6):​c.440A>C​(p.Asp147Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D147V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: USP6 NM_001304284.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.67
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304284.2. 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
	USP6	NM_001304284.2	MANE Select	c.440A>C	p.Asp147Ala	missense	Exon 15 of 38	NP_001291213.1	P35125-1
	USP6	NM_004505.4		c.440A>C	p.Asp147Ala	missense	Exon 7 of 30	NP_004496.2	P35125-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP6	ENST00000574788.6	TSL:1 MANE Select	c.440A>C	p.Asp147Ala	missense	Exon 15 of 38	ENSP00000460380.1	P35125-1
	USP6	ENST00000250066.6	TSL:1	c.440A>C	p.Asp147Ala	missense	Exon 7 of 30	ENSP00000250066.6	P35125-1
	USP6	ENST00000357482.5	TSL:1	n.886A>C		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.0011	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0033	T
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		5.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.28
Sift	Benign	0.17	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.87	P
Vest4		0.64
MutPred		0.93		Gain of MoRF binding (P = 0.0309)
MVP		0.74
MPC		0.82
ClinPred		0.76	D
GERP RS		0.86
Varity_R		0.065
gMVP		0.79

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: rs2073166493; hg19: chr17-5037237;