12-95533170-C-T

Variant names:

• chr12-95533170-C-T
• rs61733460
• NM_032147.5:c.1087G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032147.5(USP44):​c.1087G>A​(p.Gly363Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,614,146 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (17 hom.)
• Consequence: USP44 NM_032147.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.11
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016607344).
• BP6: Variant 12-95533170-C-T is Benign according to our data. Variant chr12-95533170-C-T is described in ClinVar as Benign. ClinVar VariationId is 715654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00694 (1056/152258) while in subpopulation AFR AF = 0.0241 (1001/41544). AF 95% confidence interval is 0.0229. There are 8 homozygotes in GnomAd4. There are 474 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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.1087G>A	p.Gly363Ser	missense	Exon 2 of 6	NP_115523.2	Q9H0E7
	USP44	NM_001042403.3		c.1087G>A	p.Gly363Ser	missense	Exon 2 of 6	NP_001035862.1	Q9H0E7
	USP44	NM_001278393.2		c.1087G>A	p.Gly363Ser	missense	Exon 2 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.1087G>A	p.Gly363Ser	missense	Exon 2 of 6	ENSP00000258499.3	Q9H0E7
	USP44	ENST00000393091.6	TSL:1	c.1087G>A	p.Gly363Ser	missense	Exon 2 of 6	ENSP00000376806.2	Q9H0E7
	USP44	ENST00000537435.2	TSL:1	c.1087G>A	p.Gly363Ser	missense	Exon 2 of 6	ENSP00000442629.2	Q9H0E7

Frequencies

GnomAD3 genomes AF: 0.00693 AC: 1054 AN: 152140 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00174 AC: 438 AN: 251408 AF XY: 0.00132

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000694 AC: 1014 AN: 1461888 Hom.: 17 Cov.: 30 AF XY: 0.000582 AC XY: 423 AN XY: 727244

African (AFR) AF: 0.0244 AC: 817 AN: 33480

American (AMR) AF: 0.00132 AC: 59 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112012

Other (OTH) AF: 0.00189 AC: 114 AN: 60396

GnomAD4 genome AF: 0.00694 AC: 1056 AN: 152258 Hom.: 8 Cov.: 32 AF XY: 0.00637 AC XY: 474 AN XY: 74452

African (AFR) AF: 0.0241 AC: 1001 AN: 41544

American (AMR) AF: 0.00288 AC: 44 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00258 Hom.: 12

Bravo AF: 0.00772

ESP6500AA AF: 0.0204 AC: 90

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00227 AC: 276

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	USP44-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.1
DANN	Benign	0.54
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.2	N
PhyloP100		1.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.79	N
REVEL	Benign	0.032
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.025
MVP		0.12
MPC		0.16
ClinPred		0.00094	T
GERP RS		1.5
Varity_R		0.045
gMVP		0.22
Mutation Taster		=98/2	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: rs61733460; hg19: chr12-95926946;