11-5507887-C-T

Variant names:

• chr11-5507887-C-T
• rs763691342
• NM_017481.4:c.1672G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017481.4(UBQLN3):​c.1672G>A​(p.Gly558Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: UBQLN3 NM_017481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.550

Genes affected

UBQLN3 (HGNC:12510): (ubiquilin 3) This gene encodes a ubiquitin-like protein (ubiquilin) that shares a high degree of similarity with related products in yeast, rat and frog. Ubiquilins contain an N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. They physically associate with both proteasomes and ubiquitin ligases, and are thus thought to functionally link the ubiquitination machinery to the proteasome to affect in vivo protein degradation. This gene is specifically expressed in the testis. It has been suggested that this gene may regulate cell-cycle progression during spermatogenesis, however, it has been shown that the ortholgous mouse gene is dispensable for embryonic development and spermatogenesis. [provided by RefSeq, Nov 2016]

ENSG00000239920 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04188609).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBQLN3	NM_017481.4	c.1672G>A	p.Gly558Ser	missense_variant	Exon 2 of 2	ENST00000311659.5	NP_059509.1
UBQLN3	NM_001347096.2	c.1672G>A	p.Gly558Ser	missense_variant	Exon 2 of 2		NP_001334025.1
UBQLN3	XM_011520145.3	c.1213G>A	p.Gly405Ser	missense_variant	Exon 3 of 3		XP_011518447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBQLN3	ENST00000311659.5	c.1672G>A	p.Gly558Ser	missense_variant	Exon 2 of 2	1	NM_017481.4	ENSP00000347997.2
ENSG00000239920	ENST00000380259.7	n.*739+82938G>A		intron_variant	Intron 5 of 7	5		ENSP00000369609.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248960 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134738

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461504 Hom.: 0 Cov.: 69 AF XY: 0.00000825 AC XY: 6 AN XY: 727034

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Feb 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1672G>A (p.G558S) alteration is located in exon 2 (coding exon 1) of the UBQLN3 gene. This alteration results from a G to A substitution at nucleotide position 1672, causing the glycine (G) at amino acid position 558 to be replaced by a serine (S). 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	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.37
DANN	Benign	0.61
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.68	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.015
Sift	Benign	0.28	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.058
MutPred		0.17		Gain of catalytic residue at G558 (P = 0.0374);
MVP		0.20
MPC		0.018
ClinPred		0.079	T
GERP RS		-3.3
Varity_R		0.030
gMVP		0.36

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: rs763691342; hg19: chr11-5529117;