rs1060499753

Positions:

• chr9-83683021-AT-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_013438.5(UBQLN1):​c.377del​(p.Asn126MetfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBQLN1 NM_013438.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: -0.223

Genes affected

UBQLN1 (HGNC:12508): (ubiquilin 1) This gene encodes an 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 thus are thought to functionally link the ubiquitination machinery to the proteasome to affect in vivo protein degradation. This ubiquilin has also been shown to modulate accumulation of presenilin proteins, and it is found in lesions associated with Alzheimer's and Parkinson's disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-83683021-AT-A is Pathogenic according to our data. Variant chr9-83683021-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402173.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-83683021-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBQLN1	NM_013438.5	c.377del	p.Asn126MetfsTer24	frameshift_variant	3/11	ENST00000376395.9
UBQLN1	NM_053067.3	c.377del	p.Asn126MetfsTer24	frameshift_variant	3/10
UBQLN1	XM_005251948.4	c.377del	p.Asn126MetfsTer24	frameshift_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBQLN1	ENST00000376395.9	c.377del	p.Asn126MetfsTer24	frameshift_variant	3/11	1	NM_013438.5	P3
UBQLN1	ENST00000257468.11	c.377del	p.Asn126MetfsTer24	frameshift_variant	3/10	1		A1
UBQLN1	ENST00000533705.5	n.95del		non_coding_transcript_exon_variant	2/9	1
UBQLN1	ENST00000529923.1	c.103-4423del		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

-

- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

May 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060499753; hg19: chr9-86297936;