rs1555498399

Positions:

• chr16-58014318-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000219281.8(USB1):​c.499del​(p.Thr167ProfsTer98) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USB1 ENST00000219281.8 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 4.34

Genes affected

USB1 (HGNC:25792): (U6 snRNA biogenesis phosphodiesterase 1) This gene encodes a protein with several conserved domains, however, its exact function is not known. Mutations in this gene are associated with poikiloderma with neutropenia (PN), which shows phenotypic overlap with Rothmund-Thomson syndrome (RTS) caused by mutations in the RECQL4 gene. It is believed that this gene product interacts with RECQL4 protein via SMAD4 proteins, explaining the partial clinical overlap between PN and RTS. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-58014318-GA-G is Pathogenic according to our data. Variant chr16-58014318-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 496744.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-58014318-GA-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USB1	NM_024598.4	c.499del	p.Thr167ProfsTer98	frameshift_variant	4/7	ENST00000219281.8	NP_078874.2
USB1	NM_001330568.2	c.346del	p.Thr116ProfsTer98	frameshift_variant	4/7		NP_001317497.1
USB1	NM_001195302.2	c.450-3012del		intron_variant			NP_001182231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USB1	ENST00000219281.8	c.499del	p.Thr167ProfsTer98	frameshift_variant	4/7	1	NM_024598.4	ENSP00000219281

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Poikiloderma with neutropenia Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 20, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	c.499delA was identified in four Athabaskan families [Clericuzio et al 2011]. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 496744). This variant is also known as c.496delA. This premature translational stop signal has been observed in individuals with poikiloderma with neutropenia (PMID: 21271650). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr167Profs*98) in the USB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acid(s) of the USB1 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1555498399; hg19: chr16-58048222;