4-143185715-C-T

Variant names:

• chr4-143185715-C-T
• rs1731199967
• NM_032557.6:c.265C>T

Variant summary

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

The NM_032557.6(USP38):​c.265C>T​(p.Leu89Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.85

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP38	NM_032557.6	c.265C>T	p.Leu89Phe	missense_variant	Exon 1 of 10	ENST00000307017.9	NP_115946.2
USP38	NM_001410848.1	c.265C>T	p.Leu89Phe	missense_variant	Exon 1 of 9		NP_001397777.1
USP38	NM_001290325.1	c.265C>T	p.Leu89Phe	missense_variant	Exon 1 of 9		NP_001277254.1
USP38	NM_001290326.1	c.-1217C>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.265C>T	p.Leu89Phe	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

May 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.265C>T (p.L89F) 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 265, causing the leucine (L) at amino acid position 89 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	0.27
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.19
Sift	Benign	0.096	T;T
Sift4G	Uncertain	0.013	D;D
Polyphen		0.97	.;D
Vest4		0.59
MutPred		0.31		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.90
MPC		1.9
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.54
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs1731199967; hg19: chr4-144106868;