X-133025575-A-C

Position:

• chrX-133025575-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_031907.3(USP26):​c.2646T>G​(p.Phe882Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: USP26 NM_031907.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP26	NM_031907.3	c.2646T>G	p.Phe882Leu	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.2646T>G	p.Phe882Leu	missense_variant	6/6	2	NM_031907.3	ENSP00000423390.1
USP26	ENST00000370832.1	c.2646T>G	p.Phe882Leu	missense_variant	1/1	6		ENSP00000359869.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

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

Oct 25, 2024

The c.2646T>G (p.F882L) alteration is located in exon 1 (coding exon 1) of the USP26 gene. This alteration results from a T to G substitution at nucleotide position 2646, causing the phenylalanine (F) at amino acid position 882 to be replaced by a leucine (L). 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	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.67	.;T
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.69
MutPred		0.87		Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);
MVP		0.72
MPC		0.39
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.81
gMVP		0.64

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: rs2067342502; hg19: chrX-132159603;