4-143203519-T-C

Variant names:

• chr4-143203519-T-C
• rs374790282
• NM_032557.6:c.1162T>C

Variant summary

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

The NM_032557.6(USP38):​c.1162T>C​(p.Tyr388His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,726 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USP38 NM_032557.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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.1162T>C	p.Tyr388His	missense_variant	Exon 5 of 10	ENST00000307017.9	NP_115946.2
USP38	NM_001410848.1	c.1060T>C	p.Tyr354His	missense_variant	Exon 4 of 9		NP_001397777.1
USP38	NM_001290325.1	c.1162T>C	p.Tyr388His	missense_variant	Exon 5 of 9		NP_001277254.1
USP38	NM_001290326.1	c.-320T>C		5_prime_UTR_variant	Exon 5 of 11		NP_001277255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP38	ENST00000307017.9	c.1162T>C	p.Tyr388His	missense_variant	Exon 5 of 10	1	NM_032557.6	ENSP00000303434.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460726 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726680

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1162T>C (p.Y388H) alteration is located in exon 5 (coding exon 5) of the USP38 gene. This alteration results from a T to C substitution at nucleotide position 1162, causing the tyrosine (Y) at amino acid position 388 to be replaced by a histidine (H). 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.074	.;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.61	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.0040	.;B
Vest4		0.74
MVP		0.67
MPC		0.17
ClinPred		0.75	D
GERP RS		5.0
Varity_R		0.34
gMVP		0.70

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: rs374790282; hg19: chr4-144124672;