16-58020561-C-CCT

Variant names:

• chr16-58020561-C-CCT
• rs58782258
• NM_024598.4:c.*321_*322dupCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_024598.4(USB1):​c.*321_*322dupCT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0074 (85 hom., cov: 0)
  • Exomes 𝑓: 0.0015 (11 hom.)
  • Failed GnomAD Quality Control
• Consequence: USB1 NM_024598.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0550
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00147 (337/228842) while in subpopulation AFR AF = 0.0348 (225/6460). AF 95% confidence interval is 0.0311. There are 11 homozygotes in GnomAdExome4. There are 162 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR,AD gene

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.*321_*322dupCT		3_prime_UTR	Exon 7 of 7	NP_078874.2
	USB1	NM_001195302.2		c.*321_*322dupCT		3_prime_UTR	Exon 6 of 6	NP_001182231.1	Q9BQ65-2
	USB1	NM_001330568.2		c.*321_*322dupCT		3_prime_UTR	Exon 7 of 7	NP_001317497.1	H3BNM8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USB1	ENST00000219281.8	TSL:1 MANE Select	c.*321_*322dupCT		3_prime_UTR	Exon 7 of 7	ENSP00000219281.3	Q9BQ65-1
	USB1	ENST00000561568.6	TSL:4	c.*321_*322dupCT		3_prime_UTR	Exon 7 of 7	ENSP00000457322.2	H3BTT8
	USB1	ENST00000539737.6	TSL:2	c.*321_*322dupCT		3_prime_UTR	Exon 6 of 6	ENSP00000446143.2	Q9BQ65-2

Frequencies

GnomAD3 genomes AF: 0.00736 AC: 905 AN: 122962 Hom.: 84 Cov.: 0

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.000307

Gnomad EAS AF: 0.000248

Gnomad SAS AF: 0.000294

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000260

Gnomad OTH AF: 0.00468

GnomAD4 exome AF: 0.00147 AC: 337 AN: 228842 Hom.: 11 Cov.: 0 AF XY: 0.00131 AC XY: 162 AN XY: 123944

African (AFR) AF: 0.0348 AC: 225 AN: 6460

American (AMR) AF: 0.00245 AC: 27 AN: 11000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6010

East Asian (EAS) AF: 0.000455 AC: 5 AN: 10984

South Asian (SAS) AF: 0.000613 AC: 25 AN: 40800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 876

European-Non Finnish (NFE) AF: 0.000268 AC: 35 AN: 130414

Other (OTH) AF: 0.00169 AC: 20 AN: 11838

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00741 AC: 912 AN: 123094 Hom.: 85 Cov.: 0 AF XY: 0.00786 AC XY: 460 AN XY: 58546

African (AFR) AF: 0.0280 AC: 845 AN: 30178

American (AMR) AF: 0.00346 AC: 41 AN: 11850

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 1 AN: 3258

East Asian (EAS) AF: 0.000248 AC: 1 AN: 4030

South Asian (SAS) AF: 0.00 AC: 0 AN: 3396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 202

European-Non Finnish (NFE) AF: 0.000260 AC: 16 AN: 61450

Other (OTH) AF: 0.00462 AC: 8 AN: 1732

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.055
Mutation Taster		=100/0	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs58782258;

hg19: chr16-58054465;