X-133026023-T-C

Position:

• chrX-133026023-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_031907.3(USP26):​c.2198A>G​(p.Gln733Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,097,048 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.000010 (0 hom. 4 hem.)
• Consequence: USP26 NM_031907.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.234

Genes affected

USP26 (HGNC:13485): (ubiquitin specific peptidase 26) This gene encodes a member of the ubiquitin-specific processing (UBP) family of proteases and is a deubiquitinating enzyme (DUB) with His and Cys domains. It is specifically expressed in testis tissue. Mutations in this gene have been associated with Sertoli cell-only syndrome and male infertility. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09739879).
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP26	NM_031907.3	c.2198A>G	p.Gln733Arg	missense_variant	6/6	ENST00000511190.6	NP_114113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP26	ENST00000511190.6	c.2198A>G	p.Gln733Arg	missense_variant	6/6	2	NM_031907.3	ENSP00000423390.1
USP26	ENST00000370832.1	c.2198A>G	p.Gln733Arg	missense_variant	1/1	6		ENSP00000359869.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1097048 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 4 AN XY: 362450

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: 0.0000131

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2022

The c.2198A>G (p.Q733R) alteration is located in exon 1 (coding exon 1) of the USP26 gene. This alteration results from a A to G substitution at nucleotide position 2198, causing the glutamine (Q) at amino acid position 733 to be replaced by an arginine (R). 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	0.078
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.046
DANN	Benign	0.92
DEOGEN2	Benign	0.011	T;T
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.28	.;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.097	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.97	L;L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.080
Sift	Benign	0.14	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.23	B;B
Vest4		0.029
MutPred		0.41		Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.64
MPC		0.071
ClinPred		0.21	T
GERP RS		-6.0
Varity_R		0.077
gMVP		0.16

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: rs2067345996; hg19: chrX-132160051;