4-143187940-G-A

Variant names:

• chr4-143187940-G-A
• rs771553760
• NM_032557.6:c.797G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032557.6(USP38):​c.797G>A​(p.Ser266Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000341 in 1,613,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: USP38 NM_032557.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18068945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP38	NM_032557.6	c.797G>A	p.Ser266Asn	missense_variant	Exon 2 of 10	ENST00000307017.9	NP_115946.2
USP38	NM_001410848.1	c.797G>A	p.Ser266Asn	missense_variant	Exon 2 of 9		NP_001397777.1
USP38	NM_001290325.1	c.797G>A	p.Ser266Asn	missense_variant	Exon 2 of 9		NP_001277254.1
USP38	NM_001290326.1	c.-685G>A		5_prime_UTR_variant	Exon 2 of 11		NP_001277255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP38	ENST00000307017.9	c.797G>A	p.Ser266Asn	missense_variant	Exon 2 of 10	1	NM_032557.6	ENSP00000303434.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000558 AC: 14 AN: 250962 AF XY: 0.0000811

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461240 Hom.: 0 Cov.: 31 AF XY: 0.0000550 AC XY: 40 AN XY: 726906

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33446

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44666

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26114

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39654

Gnomad4 SAS exome AF: 0.000592 AC: 51 AN: 86188

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53374

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1111676

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74460

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000829 AC: 0.000828844 AN: 0.000828844

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000577 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.797G>A (p.S266N) alteration is located in exon 2 (coding exon 2) of the USP38 gene. This alteration results from a G to A substitution at nucleotide position 797, causing the serine (S) at amino acid position 266 to be replaced by an asparagine (N). 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	Benign	-0.32	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.024	.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.061
Sift	Benign	0.66	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.0030	.;B
Vest4		0.63
MutPred		0.27		Loss of catalytic residue at S266 (P = 0.0562);Loss of catalytic residue at S266 (P = 0.0562);
MVP		0.67
MPC		0.12
ClinPred		0.10	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.48
gMVP		0.55
Mutation Taster		=53/47	polymorphism

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: rs771553760; hg19: chr4-144109093;