rs16959641

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024598.4(USB1):c.748C>G(p.Gln250Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,614,084 control chromosomes in the GnomAD database, including 5,166 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.058 ( 381 hom., cov: 31)

Exomes 𝑓: 0.077 ( 4785 hom. )

Consequence

USB1
NM_024598.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.27

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021330416).

BP6

Variant 16-58020195-C-G is Benign according to our data. Variant chr16-58020195-C-G is described in ClinVar as [Benign]. Clinvar id is 403597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USB1	NM_024598.4 link	c.748C>G	p.Gln250Glu	missense_variant	Exon 7 of 7	ENST00000219281.8	NP_078874.2	Q9BQ65-1A0A024R6V6
USB1	NM_001195302.2 link	c.694C>G	p.Gln232Glu	missense_variant	Exon 6 of 6		NP_001182231.1	Q9BQ65-2
USB1	NM_001330568.2 link	c.595C>G	p.Gln199Glu	missense_variant	Exon 7 of 7		NP_001317497.1	Q9BQ65H3BNM8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USB1	ENST00000219281.8 link	c.748C>G	p.Gln250Glu	missense_variant	Exon 7 of 7	1	NM_024598.4	ENSP00000219281.3		Q9BQ65-1

Frequencies

GnomAD3 genomes

AF:

0.0585

AC:

8904

AN:

152124

Hom.:

380

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0149

Gnomad AMI

AF:

0.118

Gnomad AMR

AF:

0.0567

Gnomad ASJ

AF:

0.0945

Gnomad EAS

AF:

0.0952

Gnomad SAS

AF:

0.0874

Gnomad FIN

AF:

0.0378

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0809

Gnomad OTH

AF:

0.0703

GnomAD3 exomes

AF:

0.0690

AC:

17355

AN:

251428

Hom.:

717

AF XY:

0.0719

AC XY:

9774

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.0126

Gnomad AMR exome

AF:

0.0351

Gnomad ASJ exome

AF:

0.0949

Gnomad EAS exome

AF:

0.101

Gnomad SAS exome

AF:

0.0816

Gnomad FIN exome

AF:

0.0408

Gnomad NFE exome

AF:

0.0817

Gnomad OTH exome

AF:

0.0741

GnomAD4 exome

AF:

0.0769

AC:

112366

AN:

1461842

Hom.:

4785

Cov.:

AF XY:

0.0775

AC XY:

56388

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0118

Gnomad4 AMR exome

AF:

0.0381

Gnomad4 ASJ exome

AF:

0.0940

Gnomad4 EAS exome

AF:

0.0736

Gnomad4 SAS exome

AF:

0.0833

Gnomad4 FIN exome

AF:

0.0419

Gnomad4 NFE exome

AF:

0.0815

Gnomad4 OTH exome

AF:

0.0734

GnomAD4 genome

AF:

0.0584

AC:

8894

AN:

152242

Hom.:

381

Cov.:

AF XY:

0.0574

AC XY:

4273

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0149

Gnomad4 AMR

AF:

0.0566

Gnomad4 ASJ

AF:

0.0945

Gnomad4 EAS

AF:

0.0947

Gnomad4 SAS

AF:

0.0867

Gnomad4 FIN

AF:

0.0378

Gnomad4 NFE

AF:

0.0809

Gnomad4 OTH

AF:

0.0701

Alfa

AF:

0.0806

Hom.:

403

Bravo

AF:

0.0575

TwinsUK

AF:

0.0779

AC:

289

ALSPAC

AF:

0.0752

AC:

290

ESP6500AA

AF:

0.0132

AC:

ESP6500EA

AF:

0.0836

AC:

719

ExAC

AF:

0.0698

AC:

8475

Asia WGS

AF:

0.0610

AC:

211

AN:

3478

EpiCase

AF:

0.0857

EpiControl

AF:

0.0852

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Poikiloderma with neutropenia

Benign:1

Aug 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.66

DEOGEN2

Benign

0.0028

T;T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.78

T;T;T

MetaRNN

Benign

0.0021

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

.;L;.

PrimateAI

Benign

0.39

PROVEAN

Benign

0.37

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.83

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.051

.;B;.

Vest4

0.092

MPC

0.25

ClinPred

0.021

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over