rs137853972

Variant names:

• chr16-58019044-CAGGAACTACAGG-C
• rs137853972
• NM_024598.4:c.683_693+1delAGGAACTACAGG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_024598.4(USB1):​c.683_693+1delAGGAACTACAGG​(p.Gln228ProfsTer35) variant causes a frameshift, splice donor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• poikiloderma with neutropenia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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 1 pathogenic variants in the truncated region.
• PP5: Variant 16-58019044-CAGGAACTACAGG-C is Pathogenic according to our data. Variant chr16-58019044-CAGGAACTACAGG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 202.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USB1	NM_024598.4	c.683_693+1delAGGAACTACAGG	p.Gln228ProfsTer35	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 6 of 7	ENST00000219281.8	NP_078874.2
USB1	NM_001195302.2	c.629_639+1delAGGAACTACAGG	p.Gln210ProfsTer35	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 5 of 6		NP_001182231.1
USB1	NM_001330568.2	c.530_540+1delAGGAACTACAGG	p.Gln177ProfsTer35	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 6 of 7		NP_001317497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USB1	ENST00000219281.8	c.683_693+1delAGGAACTACAGG	p.Gln228ProfsTer35	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 6 of 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

Jan 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Apparent frameshift variation identified by transcript analysis as affecting splicing [Volpi et al 2010]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs137853972; hg19: chr16-58052948;