rs3743559

chr16-58001525-C-Achr16-58001525-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_024598.4(USB1):c.42C>A(p.Ser14=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,608,316 control chromosomes in the GnomAD database, including 5,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (381 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4708 hom.)
• Consequence: USB1 NM_024598.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.80

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 16-58001525-C-A is Benign according to our data. Variant chr16-58001525-C-A is described in ClinVar as [Benign]. Clinvar id is 403596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USB1	NM_024598.4	c.42C>A	p.Ser14=	synonymous_variant	1/7	ENST00000219281.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USB1	ENST00000219281.8	c.42C>A	p.Ser14=	synonymous_variant	1/7	1	NM_024598.4

Frequencies

GnomAD3 genomes AF: 0.0599 AC: 9106 AN: 152102 Hom.: 380 Cov.: 32

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.0569

Gnomad ASJ AF: 0.0945

Gnomad EAS AF: 0.0942

Gnomad SAS AF: 0.0882

Gnomad FIN AF: 0.0377

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0804

Gnomad OTH AF: 0.0702

GnomAD3 exomes AF: 0.0697 AC: 16339 AN: 234572 Hom.: 663 AF XY: 0.0723 AC XY: 9272 AN XY: 128176

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.0350

Gnomad ASJ exome AF: 0.0943

Gnomad EAS exome AF: 0.101

Gnomad SAS exome AF: 0.0822

Gnomad FIN exome AF: 0.0410

Gnomad NFE exome AF: 0.0819

Gnomad OTH exome AF: 0.0743

GnomAD4 exome AF: 0.0767 AC: 111628 AN: 1456096 Hom.: 4708 Cov.: 32 AF XY: 0.0773 AC XY: 55962 AN XY: 723850

Gnomad4 AFR exome AF: 0.0173

Gnomad4 AMR exome AF: 0.0381

Gnomad4 ASJ exome AF: 0.0940

Gnomad4 EAS exome AF: 0.0736

Gnomad4 SAS exome AF: 0.0834

Gnomad4 FIN exome AF: 0.0420

Gnomad4 NFE exome AF: 0.0809

Gnomad4 OTH exome AF: 0.0736

GnomAD4 genome AF: 0.0598 AC: 9099 AN: 152220 Hom.: 381 Cov.: 32 AF XY: 0.0587 AC XY: 4367 AN XY: 74430

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.0568

Gnomad4 ASJ AF: 0.0945

Gnomad4 EAS AF: 0.0937

Gnomad4 SAS AF: 0.0875

Gnomad4 FIN AF: 0.0377

Gnomad4 NFE AF: 0.0804

Gnomad4 OTH AF: 0.0699

Alfa AF: 0.0773 Hom.: 807

Bravo AF: 0.0588

Asia WGS AF: 0.0630 AC: 218 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	1.1
Dann	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3743559; hg19: chr16-58035429; COSMIC: COSV54622308; COSMIC: COSV54622308;