2-85616314-C-T

Position:

• chr2-85616314-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006590.4(USP39):​c.119C>T​(p.Ala40Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,429,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: USP39 NM_006590.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.427

Genes affected

USP39 (HGNC:20071): (ubiquitin specific peptidase 39) Predicted to enable thiol-dependent deubiquitinase and zinc ion binding activity. Involved in spliceosomal complex assembly. Located in nucleoplasm. Part of U4/U6 x U5 tri-snRNP complex. [provided by Alliance of Genome Resources, Apr 2022]

USP39 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10758051).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP39	NM_006590.4	c.119C>T	p.Ala40Val	missense_variant	1/13	ENST00000323701.11	NP_006581.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP39	ENST00000323701.11	c.119C>T	p.Ala40Val	missense_variant	1/13	1	NM_006590.4	ENSP00000312981.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429460 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 707662

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.14e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

The c.119C>T (p.A40V) alteration is located in exon 1 (coding exon 1) of the USP39 gene. This alteration results from a C to T substitution at nucleotide position 119, causing the alanine (A) at amino acid position 40 to be replaced by a valine (V). 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	Benign	0.077
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0078	T;T;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.71	T;.;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	.;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.42	N;N;N;N
REVEL	Benign	0.028
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.34	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.17
MutPred		0.23		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP		0.54
MPC		0.22
ClinPred		0.24	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.057
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1165310963; hg19: chr2-85843437;