chr12-95518183-C-A

Variant names:

• chr12-95518183-C-A
• rs367906455
• NM_032147.5:c.2110G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032147.5(USP44):​c.2110G>T​(p.Asp704Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 152,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000039 (0 hom., cov: 32)
• Consequence: USP44 NM_032147.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13364777).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP44	NM_032147.5	MANE Select	c.2110G>T	p.Asp704Tyr	missense	Exon 6 of 6	NP_115523.2	Q9H0E7
	USP44	NM_001042403.3		c.2110G>T	p.Asp704Tyr	missense	Exon 6 of 6	NP_001035862.1	Q9H0E7
	USP44	NM_001278393.2		c.2110G>T	p.Asp704Tyr	missense	Exon 6 of 6	NP_001265322.1	Q9H0E7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP44	ENST00000258499.8	TSL:1 MANE Select	c.2110G>T	p.Asp704Tyr	missense	Exon 6 of 6	ENSP00000258499.3	Q9H0E7
	USP44	ENST00000393091.6	TSL:1	c.2110G>T	p.Asp704Tyr	missense	Exon 6 of 6	ENSP00000376806.2	Q9H0E7
	USP44	ENST00000537435.2	TSL:1	c.2110G>T	p.Asp704Tyr	missense	Exon 6 of 6	ENSP00000442629.2	Q9H0E7

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251420 AF XY: 0.0000147

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.: 30

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74320

African (AFR) AF: 0.000145 AC: 6 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.9
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.085
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.83	P
Vest4		0.32
MVP		0.45
MPC		0.58
ClinPred		0.26	T
GERP RS		3.7
Varity_R		0.19
gMVP		0.50
Mutation Taster		=99/1	polymorphism

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: rs367906455; hg19: chr12-95911959;