4-143185826-C-T

Variant names:

• chr4-143185826-C-T
• NM_032557.6:c.376C>T

Variant summary

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

The NM_032557.6(USP38):​c.376C>T​(p.Leu126Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: USP38 NM_032557.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.620

Genes affected

USP38 (HGNC:20067): (ubiquitin specific peptidase 38) Enables thiol-dependent deubiquitinase. Involved in protein deubiquitination. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.21073666).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP38	NM_032557.6	c.376C>T	p.Leu126Phe	missense_variant	Exon 1 of 10	ENST00000307017.9	NP_115946.2
USP38	NM_001410848.1	c.376C>T	p.Leu126Phe	missense_variant	Exon 1 of 9		NP_001397777.1
USP38	NM_001290325.1	c.376C>T	p.Leu126Phe	missense_variant	Exon 1 of 9		NP_001277254.1
USP38	NM_001290326.1	c.-1106C>T		5_prime_UTR_variant	Exon 1 of 11		NP_001277255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP38	ENST00000307017.9	c.376C>T	p.Leu126Phe	missense_variant	Exon 1 of 10	1	NM_032557.6	ENSP00000303434.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.376C>T (p.L126F) alteration is located in exon 1 (coding exon 1) of the USP38 gene. This alteration results from a C to T substitution at nucleotide position 376, causing the leucine (L) at amino acid position 126 to be replaced by a phenylalanine (F). 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	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	.;T
Eigen	Benign	0.019
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.070	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.10
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.99	.;D
Vest4		0.31
MutPred		0.40		Loss of stability (P = 0.0487);Loss of stability (P = 0.0487);
MVP		0.79
MPC		1.6
ClinPred		0.84	D
GERP RS		3.0
Varity_R		0.28
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-144106979;