rs137853972

Positions:

• chr16-58019044-CAGGAACTACAGG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_024598.4(USB1):​c.683_693+1delAGGAACTACAGG​(p.Gln228fs) variant causes a frameshift, splice donor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: USB1 NM_024598.4 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 5.84

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]

USB1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.144 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-58019044-CAGGAACTACAGG-C is Pathogenic according to our data. Variant chr16-58019044-CAGGAACTACAGG-C is described in ClinVar as [Pathogenic]. Clinvar id is 202.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-58019044-CAGGAACTACAGG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USB1	NM_024598.4	c.683_693+1delAGGAACTACAGG	p.Gln228fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	6/7	ENST00000219281.8	NP_078874.2
USB1	NM_001195302.2	c.629_639+1delAGGAACTACAGG	p.Gln210fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	5/6		NP_001182231.1
USB1	NM_001330568.2	c.530_540+1delAGGAACTACAGG	p.Gln177fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	6/7		NP_001317497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USB1	ENST00000219281.8	c.683_693+1delAGGAACTACAGG	p.Gln228fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	6/7	1	NM_024598.4	ENSP00000219281.3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Poikiloderma with neutropenia Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Apparent frameshift variation identified by transcript analysis as affecting splicing [Volpi et al 2010]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137853972; hg19: chr16-58052948;