Genetic Variant USP44:p.Gly418Asp (chr12-95533004-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_032147.5(USP44):c.1253G>A(p.Gly418Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)

Consequence

USP44
NM_032147.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.89

Publications

0 publications found

Variant links:

Genes affected

USP44 (HGNC:20064): (ubiquitin specific peptidase 44) The protein encoded by this gene is a protease that functions as a deubiquitinating enzyme. The encoded protein is thought to help regulate the spindle assembly checkpoint by preventing early anaphase onset. This protein specifically deubiquitinates CDC20, which stabilizes the anaphase promoting complex/cyclosome. [provided by RefSeq, Dec 2016]

USP44 Gene-Disease associations (from GenCC):

congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

USP44 links:

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ACMG classification

Classification was made for transcript

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, 0.895

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032147.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP44	NM_032147.5	MANE Select	c.1253G>A	p.Gly418Asp	missense	Exon 2 of 6	NP_115523.2	Q9H0E7
USP44	NM_001042403.3		c.1253G>A	p.Gly418Asp	missense	Exon 2 of 6	NP_001035862.1	Q9H0E7
USP44	NM_001278393.2		c.1253G>A	p.Gly418Asp	missense	Exon 2 of 6	NP_001265322.1	Q9H0E7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP44	ENST00000258499.8	TSL:1 MANE Select	c.1253G>A	p.Gly418Asp	missense	Exon 2 of 6	ENSP00000258499.3	Q9H0E7
USP44	ENST00000393091.6	TSL:1	c.1253G>A	p.Gly418Asp	missense	Exon 2 of 6	ENSP00000376806.2	Q9H0E7
USP44	ENST00000537435.2	TSL:1	c.1253G>A	p.Gly418Asp	missense	Exon 2 of 6	ENSP00000442629.2	Q9H0E7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251348

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Benign

0.042

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.6

PhyloP100

7.9

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.91

MVP

0.80

MPC

0.77

ClinPred

0.99

GERP RS

5.1

Varity_R

0.96

gMVP

0.74

Mutation Taster

=11/89

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over