12-95533004-C-T

Variant names:

• chr12-95533004-C-T
• rs138559988
• NM_032147.5:c.1253G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP44	NM_032147.5	c.1253G>A	p.Gly418Asp	missense_variant	Exon 2 of 6	ENST00000258499.8	NP_115523.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP44	ENST00000258499.8	c.1253G>A	p.Gly418Asp	missense_variant	Exon 2 of 6	1	NM_032147.5	ENSP00000258499.3
USP44	ENST00000393091.6	c.1253G>A	p.Gly418Asp	missense_variant	Exon 2 of 6	1		ENSP00000376806.2
USP44	ENST00000537435.2	c.1253G>A	p.Gly418Asp	missense_variant	Exon 2 of 6	1		ENSP00000442629.2
USP44	ENST00000552440.5	c.1253G>A	p.Gly418Asp	missense_variant	Exon 1 of 3	5		ENSP00000448670.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251348 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135846

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 SAS 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.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1253G>A (p.G418D) alteration is located in exon 2 (coding exon 1) of the USP44 gene. This alteration results from a G to A substitution at nucleotide position 1253, causing the glycine (G) at amino acid position 418 to be replaced by an aspartic acid (D). 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	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;.;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;.;D;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.6	M;M;.;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.8	D;D;D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.91
MVP		0.80
MPC		0.77
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.96
gMVP		0.74

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: rs138559988; hg19: chr12-95926780;