4-143206081-A-G

Variant names:

• chr4-143206081-A-G
• rs1049432249
• NM_032557.6:c.1258A>G

Variant summary

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

The NM_032557.6(USP38):​c.1258A>G​(p.Ser420Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: USP38 NM_032557.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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.1258A>G	p.Ser420Gly	missense_variant	Exon 6 of 10	ENST00000307017.9	NP_115946.2
USP38	NM_001410848.1	c.1156A>G	p.Ser386Gly	missense_variant	Exon 5 of 9		NP_001397777.1
USP38	NM_001290325.1	c.1258A>G	p.Ser420Gly	missense_variant	Exon 6 of 9		NP_001277254.1
USP38	NM_001290326.1	c.-108A>G		5_prime_UTR_variant	Exon 7 of 11		NP_001277255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP38	ENST00000307017.9	c.1258A>G	p.Ser420Gly	missense_variant	Exon 6 of 10	1	NM_032557.6	ENSP00000303434.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459972 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726214

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

EpiCase AF: 0.0000548

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1258A>G (p.S420G) alteration is located in exon 6 (coding exon 6) of the USP38 gene. This alteration results from a A to G substitution at nucleotide position 1258, causing the serine (S) at amino acid position 420 to be replaced by a glycine (G). 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	0.16
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.48	N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.17
Sift	Benign	0.051	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.97	.;D
Vest4		0.44
MutPred		0.30		Gain of glycosylation at S424 (P = 0.0512);Gain of glycosylation at S424 (P = 0.0512);
MVP		0.84
MPC		0.18
ClinPred		0.72	D
GERP RS		4.1
Varity_R		0.24
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1049432249; hg19: chr4-144127234;