12-95518237-T-C

Variant names:

• chr12-95518237-T-C
• rs377187350
• NM_032147.5:c.2056A>G

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.2056A>G​(p.Lys686Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. K686Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: USP44 NM_032147.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25
• Publications: 0 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=0.13440263).

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.2056A>G	p.Lys686Glu	missense	Exon 6 of 6	NP_115523.2	Q9H0E7
	USP44	NM_001042403.3		c.2056A>G	p.Lys686Glu	missense	Exon 6 of 6	NP_001035862.1	Q9H0E7
	USP44	NM_001278393.2		c.2056A>G	p.Lys686Glu	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.2056A>G	p.Lys686Glu	missense	Exon 6 of 6	ENSP00000258499.3	Q9H0E7
	USP44	ENST00000393091.6	TSL:1	c.2056A>G	p.Lys686Glu	missense	Exon 6 of 6	ENSP00000376806.2	Q9H0E7
	USP44	ENST00000537435.2	TSL:1	c.2056A>G	p.Lys686Glu	missense	Exon 6 of 6	ENSP00000442629.2	Q9H0E7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.018
Sift	Benign	0.083	T
Sift4G	Uncertain	0.018	D
Polyphen		0.24	B
Vest4		0.095
MutPred		0.42		Loss of ubiquitination at K686 (P = 0.0063)
MVP		0.51
MPC		0.22
ClinPred		0.29	T
GERP RS		3.2
Varity_R		0.091
gMVP		0.21
Mutation Taster		=95/5	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: rs377187350; hg19: chr12-95912013;