rs781151070

Variant names:

• chr16-58001495-GC-G
• rs781151070
• NM_024598.4:c.16delC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_024598.4(USB1):​c.16delC​(p.Leu6TrpfsTer45) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 1,602,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L6L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: USB1 NM_024598.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: -0.222
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• dyskeratosis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
• PP5: Variant 16-58001495-GC-G is Pathogenic according to our data. Variant chr16-58001495-GC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1453838.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024598.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USB1	NM_024598.4	MANE Select	c.16delC	p.Leu6TrpfsTer45	frameshift	Exon 1 of 7	NP_078874.2
	USB1	NM_001195302.2		c.16delC	p.Leu6TrpfsTer45	frameshift	Exon 1 of 6	NP_001182231.1	Q9BQ65-2
	USB1	NM_001204911.2		c.16delC	p.Leu6TrpfsTer45	frameshift	Exon 1 of 4	NP_001191840.1	Q9BQ65-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USB1	ENST00000219281.8	TSL:1 MANE Select	c.16delC	p.Leu6TrpfsTer45	frameshift	Exon 1 of 7	ENSP00000219281.3	Q9BQ65-1
	USB1	ENST00000539737.6	TSL:2	c.16delC	p.Leu6TrpfsTer45	frameshift	Exon 1 of 6	ENSP00000446143.2	Q9BQ65-2
	USB1	ENST00000896281.1		c.16delC	p.Leu6TrpfsTer45	frameshift	Exon 1 of 6	ENSP00000566340.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000310 AC: 7 AN: 225922 AF XY: 0.0000487

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000411

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1450486 Hom.: 0 Cov.: 31 AF XY: 0.00000694 AC XY: 5 AN XY: 720608

African (AFR) AF: 0.00 AC: 0 AN: 33258

American (AMR) AF: 0.00 AC: 0 AN: 43488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25942

East Asian (EAS) AF: 0.000179 AC: 7 AN: 39144

South Asian (SAS) AF: 0.00 AC: 0 AN: 84354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107240

Other (OTH) AF: 0.00 AC: 0 AN: 59846

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74490

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.22
Mutation Taster		=11/189	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs781151070; hg19: chr16-58035399;